Propanolamine derivatives, process for preparation of 3-n-methylamino-1-(2-thienyl)-1-propanols and process for preparation of propanolamine derivatives

ABSTRACT

The present invention provides means for preparing a racemate or an optically active substance (S- or R-isomer) of 3-N-methylamino-1-(2-thienyl)-1-propanol represented by the following general formula (I):  
                 
 
wherein R 1  represents any of a hydrogen atom, a C1-8 acyl group, a substituted or substituted C1-8 alkyloxycarbonyl group and a substituted or substituted phenyloxycarbonyl group and R 2  represents any of a hydrogen atom, a C1-8 alkyl group, a substituted or substituted benzyl group, a C1-8 acyl group, a substituted or substituted C1-8 alkyloxycarbonyl group and a substituted or substituted phenyloxycarbonyl group, with the exception that R 1  is a hydrogen atom and R 2  is a methyl group or a hydrogen atom, in a simple manner at low cost and in high yield.

TECHNICAL FIELD

The present invention relates to a novel propanolamine derivative whichis useful as an intermediate for medicines and agricultural chemicals,and to a process for preparing the same. The present invention alsorelates to a process for preparing3-N-methylamino-1-(2-thienyl)-1-propanol using a specific propanolaminederivative including the novel propanolamine derivative.

BACKGROUND ART

3-N-methylamino-1-(2-thienyl)-1-propanol is a compound which is usefulas an intermediate for medicines and agricultural chemicals.Particularly, the S-isomer is known as an essential intermediate of anantidepressant and its production process is disclosed in W. J. Wheeler,F. Kuo, Journal of Labelled Compounds and Radiopharmaceuticals, Vol.XXXVI, No. 3 (1995). This synthesis process is summarized in thefollowing scheme.

When the process described in Shin Okawara, Journal of the Society ofChemical Industry, Vol. 60, No. 9 (1957) is applied in the preparationof 3-N-methylamino-1-(2-thienyl)-1-propanol, the process by means ofdealkylation using N-bromosuccinimide described hereinafter can also beemployed. Furthermore, the process by means of dealkylation usingbromocyanine described in H. A. Hageman, Org React., 7, 198 (1953) canalso be employed.

In Jack Deeter, Jeff Frazier, Gilbert Staten, Mike Staszak, LelandWeigel, Tetrahedron Letters, 31 (49), 1990, there is reported theexample in which dealkylation is conducted using Troc and thenduloxetine is synthesized using Zn. This synthesis process is summarizedin the following scheme.

However, the process for preparing a racemate or the R-isomer of3-N-methylamino-1-(2-thienyl)-1-propanol has never been reported.

The above-mentioned process for preparing the S-isomer had the followingproblems: 1) the production cost becomes high because of numeroussynthesis steps, 2) the starting material is expensive, 3) total yieldis low, 4) expensive reducing agent must be used, and 5) columnchromatography must be used to purify the product and therefore thisprocess is not an industrial process. The process usingN-bromosuccinimide is not a process suited for industrial use becauseperoxide or ultraviolet irradiation is required and is not suited forused as an industrial process because bromocyanine is a substance havingstrong toxicity. The process using Troc is not suited for use as anindustrial process because of low yield and possibility of the presenceof metallic Zn. The process for the synthesis of duloxetine is not anindustrially efficient process because a special reducing agent is usedand optical purity is low and also the final product is purified in theform of an amine salt.

DISCLOSURE OF THE INVENTION

Under these circumstances, the present invention has been made and anobject thereof is to provide means for preparing a racemate or anoptically active substance (S- or R-isomer) of3-N-methylamino-1-(2-thienyl)-1-propanol in a simple manner at low costand at high yield.

The present inventors have intensively researched so as to achieve theabove object, and thus a novel propanolamine derivative from which3-N-methylamino-1-(2-thienyl)-1-propanol can be easily derived, and aprocess for preparing the same have been completed. Also, they havecompleted a process for preparing3-N-methylamino-1-(2-thienyl)-1-propanol in the form of a racemate or anoptically active substance, using or via a specific propanolaminederivative including a novel propanolamine derivative of the presentinvention.

The gist of the present invention is “a propanolamine derivative in theform of a racemate or an optically active substance, which isrepresented by the following general formula (I):

wherein R¹ represents any of a hydrogen atom, an acyl group having 1 to8 carbon atoms, an alkyloxycarbonyl group having 1 to 8 carbon atomswhich may have a substituent and a phenyloxycarbonyl group which mayhave a substituent, and R² represents any of a hydrogen atom, an alkylgroup having 1 to 8 carbon atoms, a benzyl group which may have asubstituent, an acyl group having 1 to 8 carbon atoms, analkyloxycarbonyl group having 1 to 8 carbon atoms which may have asubstituent and a phenyloxycarbonyl group which may have a substituent,with the exception that R¹ is a hydrogen atom and R² is a methyl groupor a hydrogen atom”.

Also the gist of the present invention is “a process for preparing3-N-methylamino-1-(2-thienyl)-1-propanol in the form of a racemate or anoptically active substance, which comprises preparing3-N-methylamino-1-(2-thienyl)-1-propanol represented by the followinggeneral formula (IV):

using or via the propanolamine derivative of the present invention”.

Also the gist of the present invention is “a process for preparing3-N-methylamino-1-(2-thienyl)-1-propanol, which comprises preparing3-N-methylamino-1-(2-thienyl)-1-propanol using or via a propanolaminederivative represented by the following general formula (III):

wherein R³ represents an alkyl group having 1 to 8 carbon atoms whichmay have a substituent or a benzyl group which may have a substituent,or a compound derived from the propanolamine derivative.

BEST MODE FOR CARRYING OUT THE INVENTION

The process for preparing 3-N-methylamino-1-(2-thienyl)-1-propanol ofthe present invention is summarized in the following scheme 1.

That is, it is a process in which a dialkylamino alcohol compound(propanolamine derivative represented by the general formula (III) or(VII)) is derived from acetylthiophene and then3-N-methylamino-1-(2-thienyl)-1-propanol is prepared through thedealkylation step I or I′.

According to this process, 3-N-methylamino-1-(2-thienyl)-1-propanol inany form of racemate, S-isomer and R-isomer can be selectively prepared.In the present specification, 3-N-methylamino-1-(2-thienyl)-1-propanolrepresented by the general formula (IV) include both the racemate andthe optically active substance. Among them, the S-isomer is representedby the general formula (VIII). To distinguish between the productionprocess of the racemate and that of the optically active substance, thecompound (IV) is shown as the racemate in the scheme 1.

According to the process of the present invention, the objectivecompound can be obtained by fewer steps without using a large amount ofan expensive reducing agent and also the objective compound can beprepared at low cost, easily within a short time, and at high yield.Particularly, when R³ is a benzyl group which may have a substituent,the objective compound can be prepared at lower cost within a shortertime because the substituent is easily eliminated.

The process of the present invention is particularly

characterized by the dealkylation steps I and I′. As shown in thefollowing scheme 2, these steps can be carried out via variousintermediates. These intermediates are characterized in that they can beprepared with high purity and can be isolated without requiring specialpurification and are also capable of preparing3-N-methylamino-1-(2-thienyl)-1-propanol represented by the generalformula (IV) without isolation. As a matter of course, the intermediatesshown in the scheme 2 are illustrative.

Various propanolamine derivatives shown in the schemes 1 and 2,including the intermediates shown in the scheme 2, are novel compounds,and the present invention provides a process for preparingaforementioned 3-N-methylamino-1-(2-thienyl)-1-propanol, these novelpropanolamine derivatives and a process for preparing the same.

The present invention will now be described in detail.

[Propanolamine Derivative]

The propanolamine derivative of the present invention is represented bythe following general formula (I):

wherein R¹ represents any of a hydrogen atom, an acyl group having 1 to8 carbon atoms, an alkyloxycarbonyl group having 1 to 8 carbon atomswhich may have a substituent and a phenyloxycarbonyl group which mayhave a substituent, and R² represents any of a hydrogen atom, an alkylgroup having 1 to 8 carbon atoms, a benzyl group which may have asubstituent, an acyl group having 1 to 8 carbon atoms, analkyloxycarbonyl group having 1 to 8 carbon atoms which may have asubstituent and a phenyloxycarbonyl group which may have a substituent,with the exception that R¹ is a hydrogen atom and R² is a methyl groupor a hydrogen atom.

Among these derivatives, a propanolamine derivative in the form of theS-isomer represented by the following general formula (XXIII):

wherein R¹ and R² are as defined above, which is useful as an essentialintermediate of an antidepressant and is capable of obtaining(S)-3-N-methylamino-1-(2-thienyl)-1-propanol, is preferable.

Specific examples of the substituent R¹ will now be described.

Examples of the acyl group having 1 to 8 carbon atoms include formylgroup, acetyl group, propanoyl group, butanoyl group, a benzoyl groupand pivaloyl group. Among these groups, an acetyl group is preferable.

Examples of the alkyloxycarbonyl group having 1 to 8 carbon atoms whichmay have a substituent include methyloxycarbonyl group, ethyloxycarbonylgroup, 2,2,2-trichloroethyloxycarbonyl group, 2-chloroethyloxycarbonylgroup, 2,2-dichloroethyloxycarbonyl group, n-propyloxycarbonyl group,iso-propyloxycarbonyl group, n-butyloxycarbonyl group,iso-butyloxycarbonyl group, sec-butyloxycarbonyl group,tert-butyloxycarbonyl group, n-pentyloxycarbonyl group,iso-pentyloxycarbonyl group, sec-pentyloxycarbonyl group,neopentyloxycarbonyl group, 1-methylbutyloxycarbonyl group,1,2-dimethylpropyloxycarbonyl group, n-hexyloxycarbonyl group,cyclohexyloxycarbonyl group, 1-methylpentyloxycarbonyl group and2-ethylbutyloxycarbonyl group. Among these groups, a2,2,2-trichloroethyloxycarbonyl group, an iso-propyloxycarbonyl groupand an iso-butyloxycarbonyl group are preferable.

Examples of the phenyloxycarbonyl group which may have a substituentinclude phenyloxycarbonyl group, chlorophenyloxycarbonyl group andtolyloxycarbonyl group. Among these groups, a phenyloxycarbonyl group ispreferable.

Specific examples of the substituent R² will now be described.

Examples of the alkyl group having 1 to 8 carbon atoms which may have asubstituent include methyl group, ethyl group, trichloroethyl group,monochloroethyl group, dichloroethyl group, n-propyl group, iso-propylgroup, n-butyl group, iso-butyl group, sec-butyl group, tert-butylgroup, n-pentyl group, iso-pentyl group, sec-pentyl group, neopentylgroup, 1-methylbutyl group, 1,2-dimethylpropyl group, n-hexyl group,1-methylpentyl group, cyclohexyl group and 2-ethylbutyl group. Amongthese groups, a methyl group is preferable, with the exception that R¹is a hydrogen atom and R² is a methyl group.

Examples of the benzyl group which may have a substituent include benzylgroup, 3,4-dimethoxybenzyl group and 2-nitrobenzyl group. Among thesegroups, a benzyl group is preferable.

Examples of the acyl group having 1 to 8 carbon atoms, thealkyloxycarbonyl group having 1 to 8 carbon atoms which may have asubstituent and the phenyloxycarbonyl group which may have a substituentinclude those which are exemplified as for the substituent R¹.

Specific examples of the propanolamine derivative of the presentinvention, which is represented by the general formula (I) or (XXIII),includeethyl(S)-N-[3-ethyloxycarbonyloxy-3-(2-thienyl)propyl]-N-methylcarbamate,ethyl(RS)-N-[3-ethyloxycarbonyloxy-3-(2-thienyl)propyl]-N-methylcarbamate,ethyl(R)-N-[3-ethyloxycarbonyloxy-3-(2-thienyl)propyl]-N-methylcarbamate,methyl(S)-N-[3-methyloxycarbonyloxy-3-(2-thienyl)propyl]-N-methylcarbamate,methyl(RS)-N-[3-methyloxycarbonyloxy-3-(2-thienyl)propyl]-N-methylcarbamate,methyl(R)-N-[3-methyloxycarbonyloxy-3-(2-thienyl)propyl]-N-methylcarbamate,2′,2′,2′-trichloroethyl(S)-N-methyl-N-[3-(2″,2″,2″-trichloroethyloxycarbonyloxy-3-(2-thienyl)propyl)carbamate,2′,2′,2′-trichloroethyl(RS)-N-methyl-N-[3-(2″,2″,2″-trichloroethyloxycarbonyloxy)-3-(2-thienyl)propyl]carbamate,2′,2′,2′-trichloroethyl(R)-N-methyl-N-[3-(2″,2″,2″-trichloroethyloxycarbonyloxy)-3-(2-thienyl)propyl]carbamate,phenyl(S)-N-methyl-N-[3-phenyloxycarbonyloxy-3-(2-thienyl)propyl]carbamate,phenyl(RS)-N-methyl-N-[3-phenyloxycarbonyloxy-3-(2-thienyl)propyl]carbamate,phenyl(R)-N-methyl-N-[3-phenyloxycarbonyloxy-3-(2-thienyl)propyl]carbamate,iso-propyl(S)-N-[3-iso-propyloxycarbonyloxy-3-(2-thienyl)propyl]-N-methylcarbamate,iso-butyl(S)-N-[3-iso-butyloxycarbonyloxy-3-(2-thienyl)propyl]-N-methylcarbamate,(S)-N,N-dimethyl-N-[3-phenyloxycarbonyloxy-3-(2-thienyl)propyl]amine,(S)-N,N-dimethyl-N-[3-iso-propyloxycarbonyloxy-3-(2-thienyl)propyl]amine,(RS)-N-[3-ethoxycarbonyloxy-3-(2-thienyl)propyl]-N,N-dimethylamine,(R)-N-[3-ethoxycarbonyloxy-3-(2-thienyl)propyl]-N,N-dimethylamine,(S)-N-[3-iso-butyloxycarbonyloxy-3-(2-thienyl)propyl]-N-benzyl-N-methylamine,(S)-N-[3-iso-butyloxycarbonyloxy-3-(2-thienyl)propyl]-N,N-dimethylamine,(RS)-N-[3-ethoxycarbonyloxy-3-(2-thienyl)propyl]-N-benzyl-N-methylamine,(R)-N-[3-ethoxycarbonyloxy-3-(2-thienyl)propyl]-N-benzyl-N-methylamine,(S)-N-[3-phenyloxycarbonyloxy-3-(2-thienyl)propyl]-N-benzyl-N-methylamine,(RS)-N-[3-phenyloxycarbonyloxy-3-(2-thienyl)propyl]-N-benzyl-N-methylamine,(S)-N-[3-hydroxy-3-(2-thienyl)propyl]-N-methylacetamide,(RS)-N-[3-hydroxy-3-(2-thienyl)propyl]-N-methylacetamide,(R)-N-[3-hydroxy-3-(2-thienyl)propyl]-N-methylacetamide,(S)-N-[3-hydroxy-3-(2-thienyl)propyl]-N-methylbutaneamide,(S)-N-[3-hydroxy-3-(2-thienyl)propyl]-N-methylbenzamide,(RS)-N-[3-hydroxy-3-(2-thienyl)propyl]-N-methylbenzamide,iso-propyl(S)-N-[3-hydroxy-3-(2-thienyl)propyl]-N-methylcarbamate,iso-butyl (S)-N-[3-hydroxy-3-(2-thienyl)propyl]-N-methylcarbamate,iso-propyl(RS)-N-[3-hydroxy-3-(2-thienyl)propyl]-N-methylcarbamate,iso-butyl(RS)-N-[3-hydroxy-3-(2-thienyl)propyl]-N-methylcarbamate,ethyl(S)-N-[3-hydroxy-3-(2-thienyl)propyl]-N-methylcarbamate,ethyl(RS)-N-[3-hydroxy-3-(2-thienyl)propyl]-N-methylcarbamate,methyl(RS)N-[3-hydroxy-3-(2-thienyl)propyl]-N-methylcarbamate, methyl(S)-N-[3-hydroxy-3-(2-thienyl)propyl]-N-methylcarbamate,phenyl(S)-N-[3-hydroxy-3-(2-thienyl)propyl]-N-methylcarbamate,phenyl(RS)-N-[3-hydroxy-3-(2-thienyl)propyl]-N-methylcarbamate,2′,2′,2′-trichloroethyl(S)-N-[3-hydroxy-3-(2-thienyl)propyl]-N-methylcarbamate,2′,2′,2′-trichloroethyl(RS)-N-[3-hydroxy-3-(2-thienyl)propyl]-N-methylcarbamate,iso-propyl(S)-N-[3-acetoxy-3-(2-thienyl)propyl]-N-methylcarbamate,iso-propyl (RS)-N-[3-acetoxy-3-(2-thienyl)propyl]-N-methylcarbamate,iso-butyl(S)-N-[3-acetoxy-3-(2-thienyl)propyl]-N-methylcarbamate,iso-butyl(RS)-N-[3-acetoxy-3-(2-thienyl)propyl]-N-methylcarbamate,cyclohexyl(S)-N-[3-acetoxy-3-(2-thienyl)propyl]-N-methylcarbamate,cyclohexyl (RS)-N-[3-acetoxy-3-(2-thienyl)propyl]-N-methylcarbamate,ethyl(S)-N-[3-acetoxy-3-(2-thienyl)propyl]-N-methylcarbamate,ethyl(RS)-N-[3-acetoxy-3-(2-thienyl)propyl]-N-methylcarbamate,methyl(S)-N-[3-acetoxy-3-(2-thienyl)propyl]-N-methylcarbamate,methyl(RS)-N-[3-acetoxy-3-(2-thienyl)propyl]-N-methylcarbamate,phenyl(S)-N-[3-acetoxy-3-(2-thienyl)propyl]-N-methylcarbamate, phenyl(RS)-N-[3-acetoxy-3-(2-thienyl)propyl]-N-methylcarbamate,phenyl(S)-N-[3-benzoyloxy-3-(2-thienyl)propyl]-N-methylcarbamate,(S)-N-[3-acetoxy-3-(2-thienyl)propyl]-N-methylacetamide,(RS)-N-[3-acetoxy-3-(2-thienyl)propyl]-N-methylacetamide,(R)-N-[3-acetoxy-3-(2-thienyl)propyl]-N-methylacetamide,(S)-N-[3-butanoyl-3-(2-thienyl)propyl]-N-methylbutaneamide,(RS)-N-[3-butanoyl-3-(2-thienyl)propyl]-N-methylbutaneamide,(S)-N-[3-benzoyloxy-3-(2-thienyl)propyl]-N-methylacetamide,(S)-N-[3-benzoyloxy-3-(2-thienyl)propyl]-N-methylbenzamide,(RS)-N-[3-benzoyloxy-3-(2-thienyl)propyl]-N-methylbenzamide,(S)-N-[3-acetoxy-3-(2-thienyl)propyl]-N-methyl-N-benzylamine,(RS)-N-[3-acetoxy-3-(2-thienyl)propyl]-N-methyl-N-benzylamine,(R)-N-[3-acetoxy-3-(2-thienyl)propyl]-N-methyl-N-benzylamine,(S)-N-[3-acetoxy-3-(2-thienyl)propyl]-N-dimethylamine,(RS)-N-[3-acetoxy-3-(2-thienyl)propyl]-N-dimethylamine,(R)-N-[3-acetoxy-3-(2-thienyl)propyl]-N-dimethylamine,phenyl(S)-N-[3-acetoxy-3-(2-thienyl)propyl]-N-methylcarbamate,phenyl(R)-N-[3-acetoxy-3-(2-thienyl)propyl]-N-methylcarbamate,phenyl(RS)-N-[3-acetoxy-3-(2-thienyl)propyl]-N-methylcarbamate,iso-propyl(S)-N-[3-acetoxy-3-(2-thienyl)propyl]-N-methylcarbamate,iso-propyl (RS)-N-[3-acetoxy-3-(2-thienyl)propyl]-N-methylcarbamate,iso-butyl(S)-N-[3-acetoxy-3-(2-thienyl)propyl]-N-methylcarbamate,iso-butyl(RS)-N-[3-acetoxy-3-(2-thienyl)propyl]-N-methylcarbamate,cyclohexyl(S)-N-[3-acetoxy-3-(2-thienyl)propyl]-N-methylcarbamate,cyclohexyl (RS)-N-[3-acetoxy-3-(2-thienyl)propyl]-N-methylcarbamate,ethyl(S)-N-[3-acetoxy-3-(2-thienyl)propyl]-N-methylcarbamate,ethyl(R)-N-[3-acetoxy-3-(2-thienyl)propyl]-N-methylcarbamate,ethyl(RS)-N-[3-acetoxy-3-(2-thienyl)propyl]-N-methylcarbamate,(S)-N-benzyl-N-methylamino-1(2-thienyl)-1-propanol,(RS)-N-benzylmethylamino-1(2-thienyl)-1-propanol,(R)-N-benzylmethylamino-1(2-thienyl)-1-propanol,(S)-N-[3-acetoxy-3-(2-thienyl)propyl]-N-methylacetamide,(R)-N-[3-acetoxy-3-(2-thienyl)propyl]-N-methylacetamide and(RS)-N-[3-acetoxy-3-(2-thienyl)propyl]-N-methylacetamide.

Among these derivatives, preferable derivatives areethyl(S)-N-[3-ethyloxycarbonyloxy-3-(2-thienyl)propyl]-N-methylcarbamate,ethyl(RS)-N-[3-ethyloxycarbonyloxy-3-(2-thienyl)propyl]-N-methylcarbamate,methyl(S)-N-[3-methyloxycarbonyloxy-3-(2-thienyl)propyl]-N-methylcarbamate,methyl(RS)-N-[3-methyloxycarbonyloxy-3-(2-thienyl)propyl]-N-methylcarbamate,2′,2′,2′-trichloroethyl(S)-N-methyl-N-[3-(2″,2″,2″-trichloroethyloxycarbonyloxy-3-(2-thienyl)propyl)carbamate,2′,2′,2′-trichloroethyl(RS)-N-methyl-N-[3-(2″,2″,2″-trichloroethyloxycarbonyloxy)-3-(2-thienyl)propyl]carbamate,phenyl(S)-N-methyl-N-[3-phenyloxycarbonyloxy-3-(2-thienyl)propyl]carbamate,phenyl(RS)-N-methyl-N-[3-phenyloxycarbonyloxy-3-(2-thienyl)propyl]carbamate,iso-propyl(S)-N-[3-iso-propyloxycarbonyloxy-3-(2-thienyl)propyl]-N-methylcarbamate,iso-butyl(S)-N-[3-iso-butyloxycarbonyloxy-3-(2-thienyl)propyl]-N-methylcarbamate,iso-propyl(RS)-N-[3-iso-propyloxycarbonyloxy-3-(2-thienyl)propyl]-N-methylcarbamate,iso-butyl(RS)-N-[3-iso-butyloxycarbonyloxy-3-(2-thienyl)propyl]-N-methylcarbamate,(RS)-N,N-dimethyl-N-[3-phenyloxycarbonyloxy-3-(2-thienyl)propyl]amine,(S)-N,N-dimethyl-N-[3-phenyloxycarbonyloxy-3-(2-thienyl)propyl]amine,(RS)-N,N-dimethyl-N-[3-iso-propyloxycarbonyloxy-3-(2-thienyl)propyl]amine,(S)-N,N-dimethyl-N-[3-iso-propyloxycarbonyloxy-3-(2-thienyl)propyl]amine,(RS)-N,N-dimethyl-N-[3-iso-butyloxycarbonyloxy-3-(2-thienyl)propyl]amine,(S)-N,N-dimethyl-N-[3-iso-butyloxycarbonyloxy-3-(2-thienyl)propyl]amine,(RS)-N-[3-ethoxycarbonyloxy-3-(2-thienyl)propyl]-N,N-dimethylamine,(S)-N-[3-ethoxycarbonyloxy-3-(2-thienyl)propyl]-N,N-dimethylamine,(S)-N-[3-iso-butyloxycarbonyloxy-3-(2-thienyl)propyl]-N-benzyl-N-methylamine,(S)-N-[3-iso-butyloxycarbonyloxy-3-(2-thienyl)propyl]-N,N-dimethylamine,(S)-N-[3-hydroxy-3-(2-thienyl)propyl]-N-methylacetamide,(RS)-N-[3-hydroxy-3-(2-thienyl)propyl]-N-methylacetamide,iso-propyl(S)-N-[3-hydroxy-3-(2-thienyl)propyl]-N-methylcarbamate,iso-butyl(S)-N-[3-hydroxy-3-(2-thienyl)propyl]-N-methylcarbamate,iso-propyl(RS)-N-[3-hydroxy-3-(2-thienyl)propyl]-N-methylcarbamate,iso-butyl (RS)-N-[3-hydroxy-3-(2-thienyl)propyl]-N-methylcarbamate,ethyl(S)-N-[3-hydroxy-3-(2-thienyl)propyl]-N-methylcarbamate,ethyl(RS)-N-[3-hydroxy-3-(2-thienyl)propyl]-N-methylcarbamate,2′,2′,2′-trichloroethyl(S)-N-[3-hydroxy-3-(2-thienyl)propyl]-N-methylcarbamate,2′,2′,2′-trichloroethyl(RS)-N-[3-hydroxy-3-(2-thienyl)propyl]-N-methylcarbamate,phenyl(S)-N-[3-hydroxy-3-(2-thienyl)propyl]-N-methylcarbamate,phenyl(RS)-N-[3-hydroxy-3-(2-thienyl)propyl]-N-methylcarbamate,(S)-N-[3-acetoxy-3-(2-thienyl)propyl]-N-methyl-N-benzylamine,(RS)-N-[3-acetoxy-3-(2-thienyl)propyl]-N-methyl-N-benzylamine,(RS)-N-[3-acetoxy-3-(2-thienyl)propyl]-N-dimethylamine,(S)-N-[3-acetoxy-3-(2-thienyl)propyl]-N-dimethylamine, phenyl(S)-N-[3-acetoxy-3-(2-thienyl)propyl]-N-methylcarbamate,phenyl(RS)-N-[3-acetoxy-3-(2-thienyl)propyl]-N-methylcarbamate,iso-propyl(S)-N-[3-acetoxy-3-(2-thienyl)propyl]-N-methylcarbamate,iso-propyl(RS)-N-[3-acetoxy-3-(2-thienyl)propyl]-N-methylcarbamate,iso-butyl (S)-N-[3-acetoxy-3-(2-thienyl)propyl]-N-methylcarbamate,iso-butyl(RS)-N-[3-acetoxy-3-(2-thienyl)propyl]-N-methylcarbamate,(S)-N-benzyl-N-methylamino- (2-thienyl)1-1-propanol,(RS)-N-benzylmethylamino-1(2-thienyl)-1-propanol,(S)-N-[3-acetoxy-3-(2-thienyl)propyl]-N-methylacetamide and(RS)-N-[3-acetoxy-3-(2-thienyl)propyl]-N-methylacetamide.

Process for preparing propanolamine derivative and3-N-methylamino-1-(2-thienyl)-1-propanol

The process for preparing the propanolamine derivative of the presentinvention, and the process for preparing3-N-methylamino-1-(2-thienyl)-1-propanol in the form of a racemate or anoptically active substance via a specific propanolamine derivativeincluding the propanolamine derivative will now be described.

As described previously, the process of the present invention issummarized in the schemes 1 and 2 and, as shown in the schemes, varioussynthetic routes exist, and thus the objective compound can be preparedthrough a desired route. Although acetylthiophene is used as a startingmaterial in the schemes, various derivatives obtained therefrom may beused as a starting material.

In the schemes 1 and 2, the substituent R³ represents an alkyl grouphaving 1 to 8 carbon atoms which may have a substituent or a benzylgroup which may have a substituent. The steps E, F and G when thesubstituent R³ is a methyl group are described in Tetrahedron Letters,31 (49), 7101-04 (1990). The step H when the substituent R³ is a methylgroup is described in Angew. Chem. Int. Ed. 40, 40-73 (2001). Therefore,in the steps of the present invention, the steps E, F, G and H are novelwhen the substituent R³ is a functional group other than a methyl group,particularly the substituent R³ is a benzyl group which may have asubstituent, while other steps are novel regardless of the structure ofthe substituent R³.

(Step E)

The step E is the step of preparing a ketone compound represented by thegeneral formula (VI) by condensing acetylthiophene and a dialkylamine(N-alkylmethylamine having 1 to 8 carbon atoms which may have asubstituent, or N-benzylmethylamine which may have a substituent)represented by the following general formula (V):HNCH₃R³  (V)wherein R³ represents an alkyl group having 1 to 8 carbon atoms whichmay have a substituent or a benzyl group which may have a substituent,and formalin (formalin source such as paraform or trioxane can also beused) in the presence of an acid catalyst (under acidic conditions).

Examples of the benzyl group which may have a substituent include benzylgroup, 3,4-dimethoxybenzyl group and 2-nitrobenzyl group.

Specific examples of N-alkylmethylamine having 1 to 8 carbon atoms whichmay have a substituent or N-benzylmethylamine which may have asubstituent used in the step E include N-ethylmethylamine,N-methyltrichloroethylamine, N-methylmonochloroethylamine,N-dichloroethylmethylamine, N-n-propylmethylamine,N-iso-propylmethylamine, N-n-butylmethylamine, N-iso-butylmethylamine,N-sec-butylmethylamine, N-tert-butylmethylamine, N-n-pentylmethylamine,N-iso-pentylmethylamine, N-sec-pentylmethylamine,N-neopentylmethylamine, N-1-methylbutylmethylamine,N-1,2-dimethylpropylmethylamine, N-n-hexylmethylamine,N-1-methylpentylmethylamine, N-2-ethylbutylmethylamine,N-benzylmethylamine, N-chlorobenzylmethylamine, and their mineral acidsalts with hydrochloric acid or the like.

The solvent used in the step E is not specifically limited as long as itdoes not exert an adverse influence on the reaction, and examplesthereof include amides such as dimethylformamide and dimethylacetamide;pyrrolidones such as N-methyl-2-pyrrolidone; ketone.sulfoxides such asacetone, ethyl methyl ketone and dimethyl sulfoxide; aromatichydrocarbons such as benzene, toluene, xylene and mesitylene; nitritessuch as acetonitrile; ethers such as diisopropyl ether, tetrahydrofuran,1,4-dioxane, 1,2-dimethoxyethane and anisole; and alcohols such asmethanol, ethanol, propanol, ethylene glycol and propylene glycol. Thesesolvents can be used alone or in combination.

The reaction temperature is preferably within a range from 0 to 150° C.,and more preferably from 30 to 100° C.

(Step F)

The step F is the step of reducing the ketone compound represented bythe general formula (VI) obtained in the step E to obtain an alcoholcompound represented by the general formula (III).

Examples of the reducing agent used in the step F include sodiumborohydride, lithium aluminum hydride and sodiumdihydrobis(2-methoxyethoxy)aluminum. Among these reducing agents, sodiumborohydride is particularly preferable.

As the reaction solvent, an organic solvent, which is inert to thereaction, can be used, and examples thereof include aromatichydrocarbons such as toluene and xylene; halogenated hydrocarbons suchas methylene chloride and chloroform; ethers such as diethyl ether,diisopropyl ether, tetrahydrofuran, 1,4-dioxane and t-butyl methylether; ester solvents such as ethyl acetate and methyl acetate; nitrilesolvents such as acetonitrile; and alcohols such as methanol, ethanol,propanol, ethylene glycol and propylene glycol. These solvents can beused alone or in combination.

The reaction temperature is preferably from −20 to 100° C., and morepreferably from 0 to 40° C. The reaction time is preferably within 12hours, and more preferably from 0.5 to 6 hours.

(Step G)

The step G is the step of obtaining a diastereomer salt of thepropanolamine derivative represented by the general formula (III)obtained in the step F with an optically active organic acid, andoptically resolving the diastereomer salt to obtain an optically activeamino alcohol. Consequently, a propanolamine derivative in the form ofthe S- or R-isomer can be obtained. The scheme 1 illustrates the casewhere the S-isomer represented by the general formula (VII) is obtained.

Examples of the optically active organic acid used in the step G includeoptically active carboxylic acid, optically active sulfonic acid andoptically active phosphonic acid, which are represented by the followinggeneral formula (XXI):

wherein D represents any of COO⁻, SO₃ ⁻ and PO₃H⁻, A, B, C eachindependently represents any of a hydrogen atom, a substituted orunsubstituted linear or branched alkyl group having 1 to 10 carbonatoms, a halogen atom, an alkoxy group, a hydroxyl group, a nitro group,a carboxyl group, a substituted or unsubstituted phenyl group and anaphthyl group, the substituent of the alkyl group, phenyl group andnaphthyl group represents any of a linear or branched alkyl group having1 to 10 carbon atoms, a halogen atom, an alkoxy group, a hydroxyl group,a nitro group, a carboxyl group and a sulfonate group, A, B, C and(CH₂)_(n)-DH are different substituents groups, n represents 1 or 0, andthe symbol * represents an asymmetric carbon. Specific examples of theoptically active carboxylic acid include optically activehydroxycarboxylic acids such as tartaric acid, malic acid, lactic acid,mandelic acid, dibenzoyltartaric acid, citramalic acid, phenyllacticacid and 1,4-benzodioxane-2-carboxylic acid, and derivatives thereof,2-bromopropionic acid, γ-carboxy-γ-butyrolactone, 2-chlorobutanoic acid,2-methylhexanoic acid, 2-methyldecanoic acid, 2-methylbutanoic acid,methyloxyacetic acid, tetrahydrofuran acid, 2-phenylbutanoic acid,2-phenylpropionic acid, 2-phenylsuccinic acid, optically activeN-substituted amino acid, pyroglutamic acid and camphoric acid.

Examples of the optically active sulfonic acid include10-camphorsulfonic acid, phenylethanesulfonic acid,α-bromocamphor-n-sulfonic acid and 3-endobromocamphor-8-sulfonic acid,and examples of the optically active phosphonic acid include1-amino-2-methylpropylphosphonic acid.

Among optically active carboxylic acids, particularly preferableoptically active carboxylic acid is an optically active2-aryl-2-substituted acetic acid represented by the general formula(XXIV):

wherein Y represents any of a linear or branched alkyl group having 1 to10 carbon atoms, a halogen atom, an alkoxy group and a hydroxyl group,Ar represents a substituted or unsubstituted phenyl group or a naphthylgroup, the substituent of Ar represents any of a linear or branchedalkyl group having 1 to 10 carbon atoms, a halogen atom, an alkoxygroup, a hydroxyl group, a nitro group, a carboxyl group and a sulfonategroup, and the symbol * represents an asymmetric carbon.

Particularly preferable examples of the optically active2-aryl-2-substituted acetic acid represented by the general formula(XXIV) include an optically active mandelic acid derivative representedby the following general formula (XXII):

wherein Z represents any of a hydrogen atom, a linear or branched alkylgroup having 1 to 10 carbon atoms, a halogen atom, an alkoxy group, ahydroxyl group, a nitro group and a benzoyl group, and the symbol *represents an asymmetric carbon.

Such an optically active mandelic acid derivative can be prepared by anyprocess, and examples thereof include processes described in JapanesePatent Application, First Publication No. Hei 4-99496 A and JapanesePatent Application, First Publication No. Hei 4-222591 A.

The optical resolution process in this step will now be described indetail.

First, a diastereomer salt of an amino alcohol in the form of a racemateobtained in the step F with an optically active organic acid is formedin a solvent. Then, a slightly soluble diastereomer salt is depositedand a solution of an optically active amino alcohol and an opticallyactive organic acid is obtained by solid liquid separation.

After dissolving the optically active organic acid in a suitablesolvent, an equimolar to 2-fold molar amount of a racemate of aminoalcohol represented by the general formula (III) is directly addeddropwise or added dropwise after diluting with a suitable solvent toform a diastereomer salt of the optically active organic acid. Theoptically active organic acid may be added to the amino alcoholrepresented by the general formula (III). The mixing temperature is notspecifically limited, but is preferably from 0 to 100° C., and morepreferably from 10 to 80° C.

The resulting salt solution is substituted or concentrated and thencooled to form a crystal. In this case, the same kind of thediastereomer salt can also be deposited by adding a small amount of asalt crystal with high optical purity as a seed crystal. The seedcrystal preferably has high optical purity and the amount is preferablyfrom about 0.01 to 1% by weight based on the amount of the solute. Evenif any seed crystal is not added, crystallization of the diastereomersalt in a supersaturated state naturally occurs to deposit the same kindof the diastereomer salt as in the case of the addition of the seedcrystal. The diastereomer salt obtained by the solid liquid separationcan be optionally recrystallized from a suitable solvent such as ethanolto form a diastereomer salt with higher optical purity.

After obtaining the diastereomer salt, as described above, an opticallyactive amino alcohol can be obtained by salt dissociation using aconventionally known process.

That is, salt dissociation is conducted by contacting a solutioncomprising an optically active amino alcohol, which is obtained byseparating the resulting diastereomer salt, an optically active organicacid and a solvent with an alkali. After cooling, solid liquidseparation is conducted to recover an optically active amino alcoholfrom the filtrate. The optical resolution is completed in the mannerdescribed above. Furthermore, the resulting optically active organicacid alkali salt is preferably contacted with a solvent and an acid todissolve in them, and cooled to form an optically active organic acid inthe form of a crystal, which is subjected to solid liquid separation torecover an optically active organic acid.

Examples of the solvent used in the optical resolution include water;various alcohols such as methanol, ethanol, isopropanol, n-propanol andbutanol; ethers such as diethyl ether, isopropylether, tetrahydrofuranand dioxane; ketones such as acetone and methyl ethyl ketone; esterssuch as methyl acetate and ethyl acetate; nitrogen-containing solventssuch as acetonitrile and dimethylformamide; halogenated hydrocarbonssuch as dichloromethane, dichloroethane and chloroform; and mixturesthereof. Among these solvents, water; various alcohols such as methanol,ethanol, isopropanol, n-propanol and butanol; and mixtures thereof arepreferable.

Examples of the alkali used in the salt dissociation of the diastereomersalt include alkali metal hydroxide, alkali earth metal hydroxide,alkali metal alcoholate and alkali earth metal alcoholate. Among thesealkalis, alkali metal hydroxide and alkali metal alcoholate arepreferable.

Examples of the acid used to recover the optically active organic acidfrom the optically active organic acid alkali salt include mineral acidssuch as hydrochloric acid, nitric acid and sulfuric acid. When water isused as the solvent, the pH is preferably 3 or lower, and morepreferably from 1 to 2, after the addition of the acid

The temperature upon the solid liquid separation is preferably 40° C. orlower, and more preferably from 0 to 10° C.

(Step H)

As described above, the optically active amino alcohol in the form ofthe S-isomer (or optically active amino alcohol in the form of theR-isomer) represented by the general formula (VII) can be prepared fromthe ketone compound represented by the general formula (VI) obtained inthe step E through the steps F and G, and also can be directly preparedfrom the ketone compound represented by the general formula (VI) throughthe step H.

The step H is the step of directly obtaining an optically active aminoalcohol by asymmetric reduction of the ketone compound represented bythe general formula (VI).

The optically active amino alcohol can be easily prepared by reactingthe ketone compound represented by the general formula (VI) obtained inthe step E with hydrogen in the presence of an asymmetricalhydrogenation catalyst containing transition metal, a base and anoptically active nitrogen-containing compound, thereby conductingasymmetrical hydrogenation of the ketone compound.

As described above, the use of three components such as asymmetricalhydrogenation catalyst containing transition metal, base and opticallyactive nitrogen-containing compound, asymmetrical hydrogenation reactionenables the reaction to proceed smoothly and high asymmetrical yield,and thus amino alcohol with sufficient reaction activity and highoptical purity can be obtained.

Examples of the asymmetrical hydrogenation catalyst used in the step Hinclude complexes of the group VIII transition metal. Among these, thosehaving an optically active ligand are preferable. Specifically, thoserepresented by the following general formula (XXV):M¹XmLn  (XXV)wherein M¹ represents group VIII transition metal such as ruthenium,rhodium, iridium, palladium or platinum, X represents a hydrogen atom, ahalogen atom, a carboxyl group, hydroxy group or an alkoxy group, Lrepresents an optically active ligand such as optically active phosphineligand or optically active organoarsenic compound ligand, and m and nrepresent an integer, are preferable.

Among these asymmetrical hydrogenation catalysts represented by thegeneral formula (XXV), those wherein M¹ as the group VIII transitionmetal is ruthenium are preferable.

Specific examples of L as the optically active ligand include2,2′-bis(diphenylphosphino)-1,1′-binaphthyl(BINAP), BINAP derivativeshaving the substituent such as alkyl group or aryl group on the naphthylring of BINAP (for example,2,2′-bis(diphenylphosphino)-6,6′-dimethyl-1,1′-binaphthyl), BINAPderivatives wherein the naphthyl ring of BINAP is partially hydrogenated(for example,2,2′-bis(diphenylphosphino)-5,6,7,8,5′,6′,7′8′-octahydro-1,1′-binaphthyl),BINAP derivatives wherein the benzene ring has 1 to 5 substituents suchas alkyl group on the phosphorus atom of BINAP (for example,2,2′-bis(di-p-tolylphosphino)-1,1′-binaphthyl),2,2′-bis(di-3,5-xylylphosphino)-1,1′-binaphthyl,2,2′-bis(dicyclohexylphosphino)-6,6′-dimethyl-1,1′-biphenyl,1-[1′,2-bis-(diphenylphosphino)ferrocenyl]ethyldiamine,2,3-bis(diphenylphosphino)butane,1-cyclohexyl-1,2-bis(diphenylphosphino)ethane,1-substituted-3,4-bis(diphenylphosphino)pyrrolidine,2,3-O-isopropylidene-2,3-dihydroxy-1,4-bis(diphenylphosphino)butane,1,2-bis[(o-methoxyphenyl)phenylphosphino]ethane,(substituted-1,2-bis(phospholano)benzene),5,6-bis(diphenylphosphino)-2-norbornene,N,N′-bis-(diphenylphosphino)-N,N′-bis(1-phenylethyl)ethylenediamine,1,2-bis(diphenylphosphino)propane and 2,4-bis(diphenylphosphino)pentane.Also PHANPHOS derivatives such as4,12-bis(diphenylphosphino)[2.2]-paracyclophane can be used. There canalso be used a monodentate optically active phosphine ligand representedby the general formula: PR¹¹R¹²R¹³ (optically active phosphine ligandwherein all of R¹¹ to R¹³ are different substituents, or opticallyactive phosphine ligand wherein at least one of R¹¹ to R¹³ is anoptically active group). Also a bidentate phosphine ligand may be used.n is preferably from 3 to 4 in the monodentate phosphine ligand, while nis preferably from 1 to 2 in the bidentate phosphine ligand.

The amount of the asymmetrical hydrogenation catalyst in the step Hvaries depending on the reaction vessel, reaction mode or economicefficiency, and a molar ratio of the amount of the asymmetricalhydrogenation catalyst to that of the carbonyl compound as a reactant ispreferably from 1/100,000 to 1/100, and more preferably from 1/10,000 to1/500. The molar ratio of less than the above range is not preferredbecause the reaction time increases, while the molar ratio of more thanthe above range is not preferred because the cost of the catalystincreases.

Examples of the base used in the step H include metal compoundsrepresented by the following general formula (XXVI):M²Y  (XXVI)wherein M² represents alkali metal or alkali earth metal and Yrepresents any of a hydroxyl group, an alkoxy group, a mercapto groupand a naphthyl group, and quaternary ammonium salts of alkali metal oralkali earth metal (for example, quaternary ammonium hydroxide).

Specific examples thereof include KOH, KOCH₃, KOCH(CH₃)₂, KC₁₀H₇, LiOH,LiOCH₃, LiOCH(CH₃)₂, (CH₃)₄N⁺OH⁻ and C₆H₅CH₂N(CH₃)₃ ⁺OH⁻.

The amount of the base is preferably from 0.5 to 100 equivalents, andmore preferably from 2 to 40 equivalents, based on the asymmetricalhydrogenation catalyst. An amount of less than the above range is notpreferred because the reaction time increases, while an amount of morethan the above range is not preferred because the catalyst is likely tobe deactivated.

Examples of the optically active nitrogen-containing compound to be usedinclude optically active amine compounds. For example, there can beexemplified amine compounds represented by the general formula:NR¹⁴R¹⁵R¹⁶, such as optically active monoamine wherein at least one ofsubstituents is an optically active group and the rest represent anygroup among a hydrogen atom, a saturated or unsaturated hydrocarbongroup and an aryl group, and optically active diamine compoundrepresented by the following general formula (XXVII):

wherein R¹⁷, R¹⁸, R²³ and R²⁴ each independently represents a hydrogenatom, a saturated or unsaturated hydrocarbon group, an aryl group, anurethane group or a sulfonyl group, R¹⁹, R²⁰, R²¹ and R²² eachindependently represents a hydrogen atom, an alkyl group, an aromaticmono- or polycyclic group, a saturated or unsaturated hydrocarbon groupor a cyclic hydrocarbon group, R¹⁹, R²⁰, R²¹ and R²² may be the same ordifferent so that carbon, to which these substituents are attached,constitutes an asymmetric center.

Specific examples thereof include optically active diamine compoundssuch as optically active 1,2-diphenylethylenediamine,1,2-cyclohexanediamine, 1,2-cycloheptanediamine,2,3-dimethylbutanediamine, 1-methyl-2,2-diphenylethylenediamine,1-isobutyl-2,2-diphenylethylenediamine,1-isopropyl-2,2-diphenylethylenediamine,1-methyl-2,2-di(p-methoxyphenyl)ethylenediamine,1-isobutyl-2,2-di(p-methoxyphenyl)ethylenediamine,1-isopropyl-2,2-di(p-methoxyphenyl)ethylenediamine,1-benzyl-2,2-di(p-methoxyphenyl)ethylenediamine,1-methyl-2,2-dinaphthylethylenediamine,1-isobutyl-2,2-dinaphthylethylenediamine and1-isopropyl-2,2-dinaphthylethylenediamine; and optically active diaminecompounds wherein one or two substituents among substituents R¹⁷ to R²³represents a sulfonyl group or an urethane group. As the opticallyactive diamine, optically active propanediamine, butanediamine andphenylene diamine derivative can be used, in addition to the exemplifiedoptically active ethylenediamine derivatives.

The amount of the optically active amine compound is preferably from 1to 4 equivalents, and more preferably from 2 to 4 equivalents, based onthe asymmetrical hydrogenation catalyst in the case of the monoaminecompound. In the case of the diamine compound, the amount is preferablyfrom 0.5 to 2.5 equivalents, and more preferably from 1 to 2equivalents. The amount of less than the above range is not preferredbecause the reaction proceeds slowly, while the amount of more than theabove range is not preferred because the catalyst is likely to bedeactivated.

In the step H, a combination of absolute structure of the opticallyactive ligand and absolute configuration of the optically activenitrogen-containing compound in the asymmetrical hydrogenation catalystis important so as to achieve high asymmetrical yield. For example,(S)-3-N-benzylmethylamino-1-(2-thienyl)-1-propanol can be obtained inhigh yield by the combination of the R-phosphine ligand and R,R-diamine.The combination of the R-phosphine ligand and S,S-diamine enables thereaction to proceed smoothly, but causes severe decrease in asymmetricalyield.

The liquid solvent used in the step H is not specifically limited aslong as it can dissolve reacting raw materials and catalysts, andexamples thereof include aromatic hydrocarbon solvents such as tolueneand xylene; aliphatic hydrocarbon solvents such as pentane and hexane;halogen-containing hydrocarbon solvents such as methylene chloride;ether solvents such as ether and tetrahydrofuran; alcohol solvents suchas methanol, ethanol, 2-propanol, butanol and benzyl alcohol; andorganic solvents containing a hetero atom such as acetonitrile, DMF andDMSO. Among these solvents, alcohol solvents are preferable because analcohol is produced. Among these solvents, 2-propanol is particularlypreferable.

The amount of the solvent to be used is decided by solubility of thereactant and economic efficiency. In the case of 2-propanol, thereaction can be conducted at a concentration of the reactant within awide range from low concentration of 1% by weight or less to theconcentration closer to no solvent, but the amount of the solvent ispreferably from 20 to 50% by weight. When the amount of the solvent isless than the above range, productivity may deteriorate. On the otherhand, when the amount of the solvent is more than the above range,catalytic action may reduced.

As the hydrogen source, a hydrogen gas, or a hydrogen donative organicor inorganic compound can be used.

In the step H, when the hydrogen gas is used, a hydrogen pressure ispreferably from 1 to 100 kg/cm², and more preferably from 3 to 30kg/cm², in terms of a relative pressure. When the hydrogen pressure islower than the above range, the reaction proceeds slowly. On the otherhand, when the hydrogen pressure is higher than the above range,economic efficiency is reduced, which is not preferred. It is possibleto maintain high activity even at low hydrogen pressure of 10 kg/cm² orlower.

Taking into account economic efficiency, the reaction temperature ispreferably from −30 to 100° C., and the reaction can be carried out evenat room temperature within a range from about 10 to 40° C. The reactiontime varies depending on reaction conditions such as reactantconcentration, temperature and pressure, and the reaction is completedwithin several minutes to 10 hours.

The reaction in the step H can also be carried out in a batch-wise orcontinuous manner.

The hydrogen donor organic or inorganic compound means a compoundcapable of donating hydrogen by means of a thermal action or a catalyticaction. Such a hydrogen donor compound is not specifically limited andpreferred examples thereof include alcohol compounds such as methanol,ethanol, 1-propanol, 2-propanol, butanol and benzyl alcohol; formic acidand salts thereof, for example, combination of amines; unsaturatedhydrocarbon or heterocyclic compounds having partially saturatedhydrocarbon, such as tetralin and decalin; hyroquinone and phosphorousacid. Among these compounds, alcohol compounds are preferable and2-propanol is more preferable.

The amount of the organic compound as the hydrogen source is preferably0.1% by weight or more in view of solubility of the reactant and ispreferably 30% by weight or less in view of economic efficiency,although the reaction can be conducted at the reactant concentrationwithin a range from 0.01% to 100% by weight. When formic acid or acombination of formic acid and an amine is used as the hydrogen source,the solvent may be used or not. When the solvent is used, aromatichydrocarbon solvents such as toluene and xylene; and organic solventscontaining hetero atom, such as acetonitrile, DMF and DMSO can be used.

3-N-methylamino-1-(2-thienyl)-1-propanol in the form of a racemate or anoptically active substance can be easily prepared from dialkylaminoalcohol (propanolamine derivative represented by the general formula(III) or (VII)), which is a propanolamine derivative in the form of theracemate or optically active substance thus obtained, via variouspropanolamine derivatives through the dealkylation step shown in thescheme 2.

(Step J)

The step J is the step of preparing a propanolamine derivative in theform of a racemate or an optically active substance represented by thefollowing general formula (XI):

by reacting a propanolamine derivative represented by the generalformula (III) with a chloroformic acid derivative represented by thefollowing general formula (IX):ClCOOR⁴  (IX)in the presence of a base. In the general formulas (IX) and (XI), R⁴represents an alkyl group having 1 to 8 carbon atoms which may have asubstituent or a phenyl group which may have a substituent.

Specific examples the chloroformic acid derivative used in the step Jinclude ethyl chloroformate, methyl chloroformate, phenyl chloroformate,2,2,2-trichloroethyl chloroformate, 2-chloroethyl chloroformate,2-iodoethyl chloroformate, butyl chloroformate, propyl chloroformate,benzyl chloroformate, nitrobenzyl chloroformate and 2,2-dichloroethylchloroformate. Among these chloroformic acid derivatives, phenylchloroformate, isopropyl chloroformate and isobutyl chloroformate aresuited for the dealkylation reaction, and isopropyl chloroformate andisobutyl chloroformate are particularly preferable because a deleterioussubstance such as phenol is not produced as a by-product.

The amount of the chloroformic acid derivative is preferably from 1 to 6mols, and more preferably from 1.5 to 4 mols, per mol of the aminoalcohol derivative represented by the general formula (III).

Examples of the base include hydroxides of amines or alkali metal ortheir salts with weak acid; hydroxides of alkali earth metal or theirsalts with weak acid; and hydroxides of quaternary ammonium or theirsalts with weak acid. Among these bases, preferable bases are ammonia;trialkylamines such as triethylamine and trimethylamine; dialkylaminessuch as dimethylamine and benzylmethylamine; monoalkylamines such asmonomethylamine; cyclic amines such as morpholine, N-methylmorpholineand piperidine; N,N-dimethylaniline, pyridine, ammonia,1,8-bis(dimethylamino)naphthalene, sodium hydroxide, potassiumhydroxide, sodium carbonate, sodium hydrogencarbonate, potassiumcarbonate, potassium hydrogencarbonate, cesium carbonate, tripotassiumphosphate and tripotassium phosphate dihydrate. The amount of the baseis preferably from 0 to 5 mols, and more preferably from 0.2 to 3 mols,per mol of the chloroformic acid derivative.

The solvent is not specifically limited as long as it does not exert anadverse influence on the reaction, and examples thereof include amidessuch as dimethylformamide and dimethylacetamide; pyrrolidones such asN-methyl-2-pyrrolidone; ketone-sulfoxides such as acetone, ethyl methylketone and dimethyl sulfoxide; aromatic hydrocarbons such as benzene,toluene, xylene and mesitylene; nitrites such as acetonitrile; andethers such as butylmethylether, diisopropyl ether, tetrahydrofuran,1,4-dioxane, 1,2-dimethoxyethane and anisole. These solvents can be usedalone or in combination thereof. The amount of the solvent isindustrially preferably from about 50 to 3000 parts by weight based on100 parts by weight of the chloroformic acid derivative in view ofoperability and economic efficiency.

The reaction temperature varies depending on the kind of the solvent,the amount of the solvent and the chloroformic acid derivative and, asthe temperature becomes higher, an increase in the amount of by-productdue to the side reaction occurs. Therefore, the reaction temperature ispreferably 100° C. or lower, and more preferably 50° C. or lower. If thetemperature is too low, deterioration of operability may be caused bysolidification of the reaction solution. Therefore, the reactiontemperature is preferably −30° C. or higher, and more preferably 0° C.or higher. By controlling the these conditions, selectivity andreactivity of the dealkylation step are remarkably improved, and thusthe objective compound can be obtained in very high yield and at highpurity. In view of the yield, purity and amount to be used, phenylchloroformate, isopropyl chloroformate and isobutyl chloroformate arepreferable, and isopropyl chloroformate and isobutyl chloroformate areparticularly preferable since a deleterious substance such as phenol isnot produced as a by-product.

(Step K)

The step K is the step of preparing a propanolamine derivativerepresented by the general formula (XV):

by reacting a propanolamine derivative represented by the generalformula (III) with an alkylcarboxylic acid chloride or alkylcarboxylicanhydride represented by the following general formula (XIII):ClCOR⁶  (XIII)or the general formula (XIV):R⁶CO)₂O  (XIV)in the presence of a base. In the general formulas (XIII), (XIV) and(XV), R⁶ represents an alkyl group having 1 to 8 carbon atoms or phenylgroup.

The acid chloride or acid anhydride serves as an acylating agent.

Specific examples of the acid chloride include acetyl chloride,propionic acid chloride, butyric acid chloride, benzoyl chloride. Amongthese acid chlorides, acetyl chloride is preferable. Specific examplesof the acid anhydride include acetic anhydride, butyric anhydride andpropionic anhydride. Among these acid anhydrides, acetic anhydride ispreferable. The amount of the acid chloride or acid anhydride ispreferably from 0.3 to 6 mols, and more preferably from 0.5 to 4 mols,per mol of the compound represented by the general formula (III).

Examples of the base include hydroxides of amines or alkali metal ortheir salts with weak acid; hydroxides of alkali earth metal or theirsalts with weak acid; and hydroxides of quaternary ammonium or theirsalts with weak acid. Among these bases, preferable bases are ammonia;trialkylamines such as triethylamine and trimethylamine; cyclic aminessuch as N-methylmorpholine and N,N′-dimethylpiperidine;N,N-dimethylaniline, pyridine, 1,8-bis(dimethylamino)naphthalene, sodiumhydroxide, potassium hydroxide, sodium carbonate, sodiumhydrogencarbonate, potassium carbonate, potassium hydrogencarbonate,cesium carbonate, tripotassium phosphate and tripotassium phosphatedihydrate. The amount of the base is preferably from 0 to 5 mols, andmore preferably from 0.2 to 3 mols, per mol of the acylating agent.

The solvent is not specifically limited as long as it does not exert anadverse influence on the reaction, and examples thereof include amidessuch as dimethylformamide and dimethylacetamide; pyrrolidones such asN-methyl-2-pyrrolidone; ketone-sulfoxides such as acetone, ethyl methylketone and dimethyl sulfoxide; aromatic hydrocarbons such as benzene,toluene, xylene and mesitylene; nitriles such as acetonitrile; etherssuch as butylmethylether, diisopropyl ether, tetrahydrofuran,1,4-dioxane, 1,2-dimethoxyethane and anisole; and water. These solventscan be used alone or in combination. The amount is not specificallylimited and is preferably from about 50 to 3000 parts by weight based on100 parts by weight of the propanolamine derivative represented by thegeneral formula (III) in view of operability and economic efficiency.

The reaction temperature is preferably from −30 to 150° C., and morepreferably from 0 to 100° C.

(Step L)

The step L is the step of preparing a propanolamine derivative in theform of a racemate or an optically active substance, which isrepresented by the general formula (XVI):

by reacting the propanolamine derivative represented by the generalformula (XV) obtained in the step K with a chloroformic acid derivativerepresented by the following general formula (IX):ClCOOR⁴  (IX)in the presence of a base. In the general formulas (IX) and (XVI), R⁴represents an alkyl group having 1 to 8 carbon atoms which may have asubstituent or a phenyl group which may have a substituent, and R⁶represents an alkyl group having 1 to 8 carbon atoms or a phenyl group.

Specific examples of the chloroformic acid derivative used in the step Linclude ethyl chloroformate, methyl chloroformate, phenyl chloroformate,butyl chloroformate, propyl chloroformate, benzyl chloroformate,nitrobenzyl chloroformate, 2,2,2-trichloroethyl chloroformate,2-chloroethyl chloroformate, 2,2-dichloroethyl chloroformate,1,1-dimethyl-2,2,2-trichloroethyl chloroformate,1,1-dimethyl-2-chloroethyl chloroformate and 1,1-dimethyl-2-bromoethylchloroformate. Among these chloroformic acid derivatives, phenylchloroformate, isopropyl chloroformate and isobutyl chloroformate arepreferable. The amount of the chloroformic acid derivative is preferablyfrom 0.5 to 5 mols, and more preferably from 0.7 to 4 mols, per mol ofthe propanolamine derivative represented by the general formula (XV).

As the base, hydroxides of amines or alkali metal or their salts withweak acid; hydroxides of alkali earth metal or their salts with weakacid; and hydroxides of quaternary ammonium or their salts with weakacid are used. Among these bases, preferable bases are ammonia,rialkylamines such as triethylamine and trimethylamine; cyclic aminessuch as N-methylmorpholine and piperidine; N,N-dimethylaniline,pyridine, 1,8-bis(dimethylamino)naphthalene, sodium hydroxide, potassiumhydroxide, sodium carbonate, sodium hydrogencarbonate, potassiumcarbonate, potassium hydrogencarbonate, cesium carbonate, tripotassiumphosphate and tripotassium phosphate dihydrate. The amount of the baseis preferably from 0 to 5 mols, and more preferably from 0.2 to 3 mols,per mol of the chloroformic acid derivative.

The solvent is not specifically limited as long as it does not exert anadverse influence on the reaction, and examples thereof include amidessuch as dimethylformamide and dimethylacetamide; pyrrolidones such asN-methyl-2-pyrrolidone; ketone.sulfoxides such as acetone, ethyl methylketone and dimethyl sulfoxide; aromatic hydrocarbons such as benzene,toluene, xylene and mesitylene; nitrites such as acetonitrile; andethers such as butylmethylether, diisopropyl ether, tetrahydrofuran,1,4-dioxane, 1,2-dimethoxyethane and anisole. These solvents can be usedalone or in combination. The amount of the solvent is industriallypreferably from about 50 to 3000 parts by weight based on 100 parts byweight of the chloroformic acid derivative in view of operability andeconomic efficiency.

The reaction temperature is preferably from −30 to 150° C., and morepreferably from 0 to 100° C.

(Step M)

The step M is the step of preparing a propanolamine derivativerepresented by the general formula (XVII):

wherein R⁶ represents an alkyl group having 1 to 8 carbon atoms or aphenyl group, by reducing the propanolamine derivative represented bythe general formula (XV) obtained in the step K.

The de(non)substitution benzylation reaction of the step M can beconducted by hydrogen reduction or hydrogen transfer reaction using acatalyst, reductive reaction using metallic sodium/liquid ammonia, orreductive reaction using DDQ. Among these reactions, the hydrogenreduction or hydrogen transfer reaction using a catalyst is preferablyemployed in view of economic efficiency and operability.

The reducing catalyst preferably contains at least one element selectedfrom nickel, cobalt, rhodium and platinum and, for example, metal orsalts such as nitrate, sulfate and chloride, and compounds such as oxideand hydroxide are preferable. These catalysts are preferable becauseless adverse influence of a catalyst poison action of sulfur is exerted.

Specific examples of preferable catalyst include platinum oxide, Raneynickel, rhodium, platinum, platinum-carbon, rhodium-platinum oxide andcobalt-silica gel. The amount of the catalyst is preferably from 1 to1/1000 parts by weight, and more preferably from 1/2 to 1/100 parts byweight, based on 100 parts by weight of the O-acyl compound representedby the general formula (XV) obtained in the step K. The catalyst can beused in the form of being supported on a carrier. As the carrier,activated carbon, silica, alumina and silica alumina or the like areused and the amount of the catalyst to be supported is preferably from 5to 70% by weight.

The reaction of the step M can be conducted in the presence of hydrogenor a hydrogen source such as formic acid or ammonium formate. In thereaction, it is preferred to use solvents which are inert to thereaction, for example, aliphatic alcohols such as methanol, ethanol,isopropanol and ethylene glycol; aliphatic ethers such asdimethoxyethane, dioxane and tetrahydrofuran; aliphatic esters such asmethyl acetate, ethyl acetate and ethyl propionate; and aromatichydrocarbons such as toluene and xylene so as to dissolve the O-acylcompound obtained in the step K. Among these solvents, aliphaticalcohols and aliphatic esters are preferable, and methanol, isopropanoland dioxane are particularly preferable in view of economic efficiency.

When the hydrogen source such as formic acid is used, the reaction canbe conducted under normal pressure. When using hydrogen, a hydrogenpressure is preferably from 1 to 200 kg/cm², and more preferably from 10to 100 kg/cm², in terms of a relative pressure.

The reaction temperature is preferably within a range from 0 to 150° C.,and more preferably from 40 to 100° C. The reaction time variesdepending on reaction conditions such as catalyst amount, reactiontemperature and hydrogen pressure, and is preferably within 30 hours,and more preferably from 0.5 to 20 hours.

(Step N)

The step N is the step of preparing a propanolamine derivativerepresented by the general formula (XVII) by conducting the cleavagereaction of the urethane moiety and the transfer reaction of the acylgroup of a propanolamine derivative represented by the following generalformula (XIX):

which is obtained by reacting a propanolamine derivative represented bythe general formula (XV) obtained in the step K, among compoundsobtained by the step L, with a chloroformic acid derivative representedby the following general formula (X).ClCOOCH₂CH_(m)X_(n)  (X)

In the general formulas (X) and (XIX), R⁶ represents an alkyl grouphaving 1 to 8 carbon atoms or a phenyl group, X represents a halogenatom, m and n each independently represents an integer of 0 to 3 and thesum of them is 3.

Examples of the cleaving agent used in the cleavage of urethane includezinc.

The solvent used in the step N is not specifically limited as long as itdoes not exert an adverse influence on the reaction, and examplesthereof include amides such as dimethylformamide and dimethylacetamide;pyrrolidones such as N-methyl-2-pyrrolidone; ketone-sulfoxides such asacetone, ethyl methyl ketone and dimethyl sulfoxide; aromatichydrocarbons such as benzene, toluene, xylene and mesitylene; nitritessuch as acetonitrile; and ethers such as butylmethylether, diisopropylether, tetrahydrofuran, 1,4-dioxane, 1,2-dimethoxyethane and anisole.These solvents can be used alone or in combination. The amount of thesolvent is industrially preferably from about 50 to 3000 parts by weightbased on 100 parts by weight of the propanolamine derivative representedby the general formula (XIX) in view of operability and economicefficiency.

The pH in the reaction system is preferably from 1 to 9, and morepreferably from 2 to 8. The reaction temperature is preferably from −30to 150° C., and more preferably from 0 to 100° C.

(Step O)

The step O is the step of preparing a propanolamine derivativerepresented by the general formula (XII):

wherein R⁴ represents an alkyl group having 1 to 8 carbon atoms whichmay have a substituent or a phenyl group which may have a substituent,by treating the propanolamine derivative represented by the generalformula (XI) obtained in the step J with a base.

Examples of the base used in the step O include hydroxides of alkalimetal or their salts with weak acid; hydroxides of alkali earth metal ortheir salts with weak acid; and hydroxides of quaternary ammonium ortheir salts with weak acid. Specific examples thereof include sodiumhydroxide, potassium hydroxide, sodium carbonate, sodiumhydrogencarbonate, potassium carbonate, potassium hydrogencarbonate,cesium carbonate, tripotassium phosphate, tripotassium phosphatedihydrate. The amount of the base is preferably from 1 to 10 mols, andmore preferably from 2 to 6 mols, per mol of the compound represented bythe general formula (XI) obtained in the step J.

The solvent is not specifically limited as long as it does not exert anadverse influence on the reaction, and examples thereof include amidessuch as dimethylformamide and dimethylacetamide; pyrrolidones such asN-methyl-2-pyrrolidone; ketone-sulfoxides such as acetone, ethyl methylketone and dimethyl sulfoxide; aromatic hydrocarbons such as benzene,toluene, xylene and mesitylene; ethers such as butyl methyl ether,diisopropyl ether, tetrahydrofuran, 1,4-dioxane, 1,2-dimethoxyethane andanisole; and water. These solvents can be used alone or in combination.The amount of the solvent is industrially preferably from about 50 to3000 parts by weight based on 100 parts by weight of theN,O-bis(alkoxycarbonyl) compound represented by the general formula (XI)in view of operability and economic efficiency. When using the solventother than water, a suitable amount of water is preferably used. Theamount of water is preferably from 1 to 10000 mols, and more preferablyfrom 2 to 6000 mols, per mol of the N,O-bis(alkoxycarbonyl) compoundrepresented by the general formula (XI). The reaction temperature ispreferably from −30 to 100° C., and more preferably from 0 to 90° C.

(Step of P)

The step P is the step of preparing a propanolamine derivativerepresented by the general formula (XVIII):

by reacting the propanolamine derivative represented by the generalformula (XVII) in the step M or N with an alkylcarboxylic acid chlorideor alkylcarboxylic anhydride represented by the following generalformula (XIII):ClCOR⁶  (XII)or the general formula (XIV):(R⁶CO)₂O  (XIV)in the presence of a base. The acid chloride or acid anhydride serves asan acylating agent.

Examples of the acid chloride include acetyl chloride, propionic acidchloride, butyric acid chloride and benzoyl chloride. Among these acidchlorides, acetyl chloride is preferable. Examples of the acid anhydrideinclude acetic anhydride, butyric anhydride and propionic anhydride.Among these acid anhydrides, acetic anhydride is preferable. The amountof the acid chloride or acid anhydride is preferably from 0.3 to 6 mols,and more preferably from 0.5 to 4 mols, per mol of the compoundrepresented by the general formula (XVII).

Examples of the base include amines; hydroxides of alkali metal or theirsalts with weak acid; hydroxides of alkali earth metal or their saltswith weak acid; and hydroxides of quaternary ammonium or their saltswith weak acid. Specific examples thereof include trialkylamines such asammonia, triethylamine and trimethylamine; cyclic amines such asN-methylmorpholine and N,N′-dimethylpiperidine; N,N-dimethylaniline,pyridine, 1,8-bis(dimethylamino)naphthalene, sodium hydroxide, potassiumhydroxide, sodium carbonate, sodium hydrogencarbonate, potassiumcarbonate, potassium hydrogencarbonate, cesium carbonate, tripotassiumphosphate and tripotassium phosphate dihydrate. The amount of the baseis preferably from 0 to 5 mols, and more preferably from 0.2 to 3 mols,per mol of the chloroformic acid derivative.

The solvent is not specifically limited as long as it does not exert anadverse influence on the reaction, and examples thereof include amidessuch as dimethylformamide and dimethylacetamide; pyrrolidones such asN-methyl-2-pyrrolidone; ketone-sulfoxides such as acetone, ethyl methylketone and dimethyl sulfoxide; aromatic hydrocarbons such as benzene,toluene, xylene and mesitylene; nitrites such as acetonitrile; etherssuch as butyl methyl ether, diisopropyl ether, tetrahydrofuran,1,4-dioxane, 1,2-dimethoxyethane and anisole; and water. These solventscan be used alone or in combination. The amount of the solvent is notspecifically limited, and is industrially preferably from about 50 to3000 parts by weight based on 100 parts by weight of the propanolaminederivative represented by the general formula (XVII) in view ofoperability and economic efficiency.

The reaction temperature is preferably from −30 to 150° C., and morepreferably from 0 to 100° C.

(Step Q)

The step Q is the step of preparing3-N-methylamino-1-(2-thienyl)-1-propanol represented by the generalformula (IV) by hydrolyzing the propanolamine derivative represented bythe general formula (XII) obtained in the step O in the presence of abase. The hydrolysis reaction is easily handled because heavy metal suchas Zn is not required.

Examples of the base used in the step Q include hydroxides of alkalimetal or their salts with weak acid; hydroxides of alkali earth metal ortheir salts with weak acid; and hydroxides of quaternary ammonium ortheir salts weak acid. Specific examples thereof include sodiumhydroxide, potassium hydroxide, sodium carbonate, sodiumhydrogencarbonate, potassium carbonate, potassium hydrogencarbonate,cesium carbonate, tripotassium phosphate and tripotassium phosphatedihydrate. The amount of the base is preferably from 1 to 10 mols, andmore preferably from 2 to 6 mols, per mol of the N-alkoxycarbonylalcoholcompound represented by the general formula (XII) obtained in the stepO.

The solvent is not specifically limited as long as it does not exert anadverse influence on the reaction, and examples thereof include alcoholssuch as methanol, ethanol, propanol, isopropanol and butanol; amidessuch as dimethylformamide and dimethylacetamide; pyrrolidones such asN-methyl-2-pyrrolidone; ketone-sulfoxides such as acetone, ethyl methylketone and dimethyl sulfoxide; aromatic hydrocarbons such as benzene,toluene, xylene and mesitylene; ethers such as butyl methyl ether,diisopropyl ether, tetrahydrofuran, 1,4-dioxane, 1,2-dimethoxyethane andanisole; and water. These solvents can be used alone or in combination.The amount of the solvent is industrially preferably from about 50 to3000 parts by weight based on 100 parts by weight of theN-alkoxycarbonyl alcohol compound represented by the general formula(XII) in view of operability and economic efficiency. When using asolvent other than water, a suitable amount of water can be addedthereto. The amount of water is preferably from 1 to 10000 mols, andmore preferably from 2 to 6000 mols, per mol of the N-alkoxycarbonylalcohol compound represented by the general formula (XII). The reactiontemperature is preferably from 0 to 200° C., and more preferably from 10to 120° C.

(Step R)

The step R is the step of preparing3-N-methylamino-1-(2-thienyl)-1-propanol represented by the generalformula (IV) by hydrolyzing the propanolamine derivative represented bythe general formula (XI) obtained in the step J in the presence of abase. By the hydrolysis in the presence of the base, a hydroxyl groupand an urethane group of the propanolamine derivative represented by thegeneral formula (XI) can be simultaneously deprotected to prepare3-N-methylamino-1-(2-thienyl)-1-propanol represented by the generalformula (IV). The hydrolysis reaction is easily handled because heavymetal such as Zn is not required.

Examples of the base used in the step R include hydroxides of alkalimetal or their salts with weak acid; hydroxides of alkali earth metal ortheir salts with weak acid; and hydroxides of quaternary ammonium ortheir salts with weak acid. Specific examples thereof include sodiumhydroxide, potassium hydroxide, sodium carbonate, sodiumhydrogencarbonate, potassium carbonate, potassium hydrogencarbonate,cesium carbonate, tripotassium phosphate and tripotassium phosphatedihydrate. The amount of the base is preferably from 1 to 10 mols, andmore preferably from 2 to 6 mols, per mol of the N,O-bis(alkoxycarbonyl)compound represented by the general formula (XI).

The solvent is not specifically limited as long as it does not exert anadverse influence on the reaction, and examples thereof include alcoholssuch as methanol, ethanol, propanol, isopropanol and butanol; amidessuch as dimethylformamide and dimethylacetamide; pyrrolidones such asN-methyl-2-pyrrolidone; ketone.sulfoxides such as acetone, ethyl methylketone and dimethyl sulfoxide; aromatic hydrocarbons such as benzene,toluene, xylene and mesitylene; ethers such as butyl methyl ether,diisopropyl ether, tetrahydrofuran, 1,4-dioxane, 1,2-dimethoxyethane andanisole; and water. These solvents can be used alone or in combination.The amount of the solvent is industrially preferably from about 50 to3000 parts by weight based on 100 parts by weight of theN,O-bis(alkoxycarbonyl) compound represented by the general formula (XI)in view of operability and economic efficiency. When using the solventother than water, a suitable amount of water can also be added thereto.The amount of water is preferably from 0 to 10000 mols, and morepreferably from 2 to 6000 mols, per mol of the N,O-bis(alkoxycarbonyl)compound represented by the general formula (XI).

The reaction temperature is preferably from 0 to 200° C., and morepreferably from 10 to 150° C.

(Step S)

The step S can be roughly classified into three steps, for example,steps S-1, S-2 and S-3, and these steps will now be described,respectively.

<Step S-1>

The step S-1 is the step of preparing3-N-methylamino-1-(2-thienyl)-1-propanol represented by the generalformula (IV) by reductively eliminating the substituent R³ of apropanolamine derivative represented by the general formula (III).

The de(non)substitution benzylation reaction of this step can beconducted by a hydrogen reduction or hydrogen transfer reaction using acatalyst, a reductive reaction using metallic sodium/liquid ammonia or areductive reaction using DDQ. Among these reactions, the hydrogenreduction or hydrogen transfer reaction using the catalyst is preferablyemployed in view of economic efficiency and operability.

The reducing catalyst preferably contains at least one element selectedfrom nickel, cobalt, rhodium and platinum and, for example, metal orsalts such as nitrate, sulfate and chloride, and compounds such as oxideand hydroxide are preferable. These catalysts are preferable becauseless adverse influence of a catalyst poison action of sulfur is exerted.

Specific examples of preferable catalyst include platinum oxide, Raneynickel, rhodium, platinum, platinum-carbon, rhodium-platinum oxide andcobalt-silica gel. The amount of the catalyst is preferably from 10 to1/1000 parts by weight, and more preferably from 5 to 1/100 parts byweight, based on 100 parts by weight of the compound represented by thegeneral formula (III). The catalyst can be used in the form of beingsupported on a carrier. As the carrier, activated carbon, silica,alumina and silica alumina are used and the amount of the catalyst to besupported is preferably from 5 to 70% by weight.

The reaction can be conducted in the presence of hydrogen or a hydrogensource such as formic acid or ammonium formate. In the reaction, it ispreferred to use solvents which are inert to the reaction, for example,aliphatic alcohols such as methanol, ethanol, isopropanol and ethyleneglycol; aliphatic ethers such as dimethoxyethane, dioxane andtetrahydrofuran; and aliphatic esters such as methyl acetate, ethylacetate and ethyl propionate; and aromatic hydrocarbons such as tolueneand xylene so as to dissolve the compound represented by the generalformula (III). Among these solvents, aliphatic alcohols and aliphaticesters are preferable, and methanol, isopropanol and dioxane areparticularly preferable in view of economic efficiency.

When the hydrogen source such as formic acid is used, the reaction canbe conducted under normal pressure. When using hydrogen, a hydrogenpressure is preferably from 1 to 200 kg/cm², and more preferably from 10to 100 kg/cm², in terms of a relative pressure. The reaction temperatureis preferably within a range from 0 to 180° C., and more preferably from40 to 150° C. The reaction time varies depending on reaction conditionssuch as catalyst amount, reaction temperature and hydrogen pressure, andis preferably within 500 hours, and more preferably from 0.5 to 400hours.

<Step S-2>

The step S-2 is the step of preparing3-N-methylamino-1-(2-thienyl)-1-propanol represented by the generalformula (IV) by reacting a propanolamine derivative represented by thegeneral formula (III) with a chloroformic acid derivative represented bythe following general formula (IX):ClCOOR⁴  (IX)wherein R⁴ represents an alkyl group having 1 to 8 carbon atoms whichmay have a substituent or a phenyl group which may have a substituent,in the presence of a base, and hydrolyzing the intermediate withoutisolation. In this case, the intermediate can be subjected to thefollowing hydrolysis step without protecting a hydroxyl group of thepropanolamine derivative represented by the general formula (III) withanother protective group and 3-N-methylamino-1-(2-thienyl)-1-propanolcan be easily prepared, and therefore this is superior step.

Specific examples of the chloroformic acid derivative used in this stepinclude ethyl chloroformate, methyl chloroformate, phenyl chloroformate,2,2,2-trichloroethyl chloroformate, 2-chloroethyl chloroformate,2-iodoethyl chloroformate, butyl chloroformate, propyl chloroformate,benzyl chloroformate, nitrobenzyl chloroformate, 2,2,2-trichloroethylchloroformate, 2-chloroethyl chloroformate, 2,2-dichloroethylchloroformate, 1,1-dimethyl-2,2,2-trichloroethyl chloroformate,1,1-dimethyl-2-chloroethyl chloroformate and 1,1-dimethyl-2-bromoethylchloroformate. Among these chloroformic acid derivatives,phenylchloroformate, iso-propylchloroformate and iso-butylchloroformateare preferable. The amount of the chloroformic acid derivative ispreferably from 1 to 6 mols, and more preferably from 1.5 to 4 mols, permol of the amino alcohol derivative represented by the general formula(III).

Examples of the base used in the step of reacting a propanolaminederivative represented by the general formula (III) with a chloroformicacid derivative include amines; hydroxides of alkali metal or theirsalts with weak acid; hydroxides of alkali earth metal or their saltswith weak acid; and hydroxides of quaternary ammonium or their saltswith weak acid. Among these bases, preferable bases are ammonia;trialkylamines such as triethylamine and trimethylamine; dialkylaminessuch as dimethylamine and benzylmethylamine; monoalkylamines such asmonomethylamine; cyclic amines such as morpholine, N-methylmorpholineand piperidine; N,N-dimethylaniline, pyridine, ammonia,1,8-bis(dimethylamino)naphthalene, sodium hydroxide, potassiumhydroxide, sodium carbonate, sodium hydrogencarbonate, potassiumcarbonate, potassium hydrogencarbonate, cesium carbonate, tripotassiumphosphate and tripotassium phosphate dihydrate. The amount of the baseis preferably from 0 to 5 mols, and more preferably from 0.2 to 3 mols,per mol of the chloroformic acid derivative.

The solvent used in the step of reacting a propanolamine derivativerepresented by the general formula (III) with a chloroformic acidderivative is not specifically limited as long as it does not exert anadverse influence on the reaction, and examples thereof include amidessuch as dimethylformamide and dimethylacetamide; pyrrolidones such asN-methyl-2-pyrrolidone; ketone-sulfoxides such as acetone, ethyl methylketone and dimethyl sulfoxide; aromatic hydrocarbons such as benzene,toluene, xylene and mesitylene; nitriles such as acetonitrile; andethers such as t-butyl methyl ether, diisopropyl ether, tetrahydrofuran,1,4-dioxane, 1,2-dimethoxyethane and anisole. When the replacement ofthe solvent is not conducted in the following hydrolysis step, aromatichydrocarbons such as benzene, toluene, xylene and mesitylene; and etherssuch as t-butyl methyl ether, diisopropyl ether, tetrahydrofuran,1,4-dioxane, 1,2-dimethoxyethane and anisole are preferable. Thesesolvents can be used alone or in combination. The amount of the solventis industrially preferably from about 50 to 3000 parts by weight basedon 100 parts by weight of the chloroformic acid derivative in view ofoperability and economic efficiency.

The reaction temperature in the step of reacting a propanolaminederivative represented by the general formula (III) with a chloroformicacid derivative varies depending on the kind of the solvent, the amountof the solvent and the chloroformic acid derivative and, as thetemperature becomes higher, an increase in the amount of by-product dueto the side reaction occurs. Therefore, the reaction temperature ispreferably 100° C. or lower, and more preferably 50° C. or lower. If thetemperature is too low, deterioration of operability may be caused bysolidification of the reaction solution. Therefore, the reactiontemperature is preferably −30° C. or higher, and more preferably 0° C.or higher. By controlling these conditions, selectivity and reactivityof the dealkylation step are remarkably improved, and thus the objectivecompound can be obtained in very high yield and at high purity. In viewof the yield, purity and amount to be used, phenyl chloroformate,isopropyl chloroformate and isobutyl chloroformate are preferable, andisopropyl chloroformate and isobutyl chloroformate are particularlypreferable since a deleterious substance such as phenol is not producedas by-product.

Examples of the base used in the hydrolysis step include hydroxides ofalkali metal or their salts with weak acid; hydroxides of alkali earthmetal or their salts with weak acid; and hydroxides of quaternaryammonium or their salts with weak acid. Specific examples thereofinclude sodium hydroxide, potassium hydroxide, sodium carbonate, sodiumhydrogencarbonate, potassium carbonate, potassium hydrogencarbonate,cesium carbonate, tripotassium phosphate and tripotassium phosphatedihydrate. Among these bases, hydroxides of alkali metal such as sodiumhydroxide and potassium hydroxide are preferable. The amount of the baseis preferably from 1 to 10 mols, and more preferably from 2 to 6 mols,per mol of the chloroformic acid derivative.

The solvent used in the hydrolysis step is not specifically limited aslong as it does not exert an adverse influence on the reaction, andexamples thereof include alcohols such as methanol, ethanol, propanol,isopropanol and butanol; amides such as dimethylformamide anddimethylacetamide; pyrrolidones such as N-methyl-2-pyrrolidone;ketone-sulfoxides such as acetone, ethyl methyl ketone and dimethylsulfoxide; aromatic hydrocarbons such as benzene, toluene, xylene andmesitylene; ethers such as butyl methyl ether, diisopropyl ether,tetrahydrofuran, 1,4-dioxane, 1,2-dimethoxyethane and anisole; andwater. These solvents can be used alone or in combination. The amount ofthe solvent is industrially preferably from about 50 to 3000 parts byweight based on 100 parts by weight of the compound represented by thegeneral formula (III) in view of operability and economic efficiency.When using the solvent other than water, a suitable amount of water canalso be added thereto. The amount of water is preferably from 0 to 10000mols, and more preferably from 0 to 6000 mols, per mol of the compoundrepresented by the general formula (III).

The reaction temperature of the hydrolysis step is preferably from 0 to200° C., and more preferably from 10 to 150° C.

<Step S-3>

The step S-3 is the step of preparing3-N-methylamino-1-(2-thienyl)-1-propanol represented by the generalformula (IV) by reacting a propanolamine derivative represented by thegeneral formula (III) with a chloroformic acid derivative represented bythe following general formula (X):ClCOOCH₂CH_(m)X_(n)  (X)wherein X represents a halogen atom, m and n each independentlyrepresents an integer of 0 to 3 and the sum of them is 3, in thepresence of a base, and subjecting the intermediate todehalogenation/alkyloxycarbonylation and hydrolysis without isolation.

Specific examples of the chloroformic acid derivative used in this stepinclude 2,2,2-trichloroethyl chloroformate, 2-chloroethyl chloroformate,2,2-dichloroethyl chloroformate, 1,1-dimethyl-2,2,2-trichloroethylchloroformate, 1,1-dimethyl-2-chloroethyl chloroformate and1,1-dimethyl-2-bromoethyl chloroformate. Among these chloroformic acidderivatives, 2,2,2-trichloroethyl chloroformate is preferable. Theamount of the chloroformic acid derivative is preferably from 0.5 to 5mols, and more preferably from 0.7 to 4 mols, per mol of the aminoalcohol derivative represented by the general formula (III).

Examples of the base used in the step of reacting a propanolaminederivative represented by the general formula (III) with a chloroformicacid derivative include amines; hydroxides of alkali metal or theirsalts with weak acid; hydroxides of alkali earth metal or their saltswith weak acid; and hydroxides of quaternary ammonium or their saltswith weak acid. Among these bases, preferable bases are ammonia;trialkylamines such as triethylamine and trimethylamine; cyclic aminessuch as N-methylmorpholine and piperidine; N,N-dimethylaniline,pyridine, 1,8-bis(dimethylamino)naphthalene, sodium hydroxide, potassiumhydroxide, sodium carbonate, sodium hydrogencarbonate, potassiumcarbonate, potassium hydrogencarbonate, cesium carbonate, tripotassiumphosphate and tripotassium phosphate dihydrate. The amount of the baseis preferably from 0 to 5 mols, and more preferably from 0.2 to 3 mols,per mol of the chloroformic acid derivative.

The solvent used in the step of reacting a propanolamine derivativerepresented by the general formula (III) with a chloroformic acidderivative is not specifically limited as long as it does not exert anadverse influence on the reaction, and examples thereof include amidessuch as dimethylformamide and dimethylacetamide; pyrrolidones such asN-methyl-2-pyrrolidone; ketone-sulfoxides such as acetone, ethyl methylketone and dimethyl sulfoxide; aromatic hydrocarbons such as benzene,toluene, xylene and mesitylene; nitriles such as acetonitrile; andethers such as butyl methyl ether, diisopropyl ether, tetrahydrofuran,1,4-dioxane, 1,2-dimethoxyethane and anisole. These solvents can be usedalone or in combination. The amount of the solvent is industriallypreferably from about 50 to 3000 parts by weight based on 100 parts byweight of the chloroformic acid derivative in view of operability andeconomic efficiency.

The reaction temperature in the step of reacting a propanolaminederivative represented by the general formula (III) with a chloroformicacid derivative is preferably from −30 to 150° C., and more preferablyfrom 0 to 100° C.

In the propanolamine derivative obtained in the step of reacting apropanolamine derivative represented by the general formula (III) with achloroformic acid derivative, the dealkoxycarbonylation of the carbamatemoiety can be easily conducted reductively without isolation.Simultaneously, transfer of an acyl group can be conducted, and thus thepropanolamine derivative can be easily converted into an N-acyl compoundin the form of a racemate or an optically active substance.

Examples of the dealkoxycarbonylating agent of the carbamate moietyinclude zinc/acetic acid, sodium/ammonia, boron trifluorideetherate/trifluoroacetic acid and alcohol. Among thesedealkoxycarbonylating agents, zinc/acetic acid is preferable.

Examples of the solvent used in the dealkoxycarbonylation step includesolvents exemplified in the step of reacting a propanolamine derivativerepresented by the general formula (III) with a chloroformic acidderivative.

The pH in the reaction system in the dealkoxycarbonylation step ispreferably from 1 to 9, and more preferably from 2 to 8. The reactiontemperature is preferably from −30 to 150° C., and more preferably from0 to 100° C.

(Step T)

The step T is the step of preparing3-N-methylamino-1-(2-thienyl)-1-propanol in the form of a racemate or anoptically active substance by hydrolyzing O-acyl N-alkoxycarbonylcompound in the form of a racemate or an optically active substance,which is represented by general formula (XVI), obtained in the step L inthe presence of a base.

Examples of the base used in the step T include hydroxide of alkalimetal or their salts with weak acid; hydroxides of alkali earth metal ortheir salts with weak acid; and hydroxides of quaternary ammonium ortheir salts with weak acid. Specific examples thereof include sodiumhydroxide, potassium hydroxide, sodium carbonate, sodiumhydrogencarbonate, potassium carbonate, potassium hydrogencarbonate,cesium carbonate, tripotassium phosphate and tripotassium phosphatedihydrate. The amount of the base is preferably from 1 to 10 mols, andmore preferably from 2 to 6 mols, per mol of the O-acyl N-alkoxycarbonylcompound represented by the general formula (XVI).

The solvent is not specifically limited as long as it does not exert anadverse influence on the reaction, and examples thereof include alcoholssuch as methanol, ethanol, propanol, isopropanol and butanol; amidessuch as dimethylformamide and dimethylacetamide; pyrrolidones such asN-methyl-2-pyrrolidone; ketone-sulfoxides such as acetone, ethyl methylketone and dimethyl sulfoxide; aromatic hydrocarbons such as benzene,toluene, xylene and mesitylene; ethers such as butyl methylether,diisopropyl ether, tetrahydrofuran, 1,4-dioxane, 1,2-dimethoxyethane andanisole; and water. These solvents can be used alone or in combination.The amount of the solvent is industrially preferably from about 50 to3000 parts by weight based on 100 parts by weight of the O-acylN-alkoxycarbonyl compound represented by the general formula (XVI) inview of operability and economic efficiency. When using the solventother than water, a suitable amount of water can also be added thereto.The amount of water is preferably from 1 to 10000 mols, and morepreferably from 2 to 6000 mols, per mol of the O-acyl N-alkoxycarbonylcompound represented by the general formula (XVI).

The reaction temperature is preferably from 0 to 200° C., and morepreferably from 10 to 150° C.

(Step U)

The step U is the step of preparing3-N-methylamino-1-(2-thienyl)-1-propanol represented by the generalformula (IV) by hydrolyzing the propanolamine derivative represented bythe general formula (XVIII) obtained in the step P in the presence of abase.

Examples of the base used in the step U include hydroxides of alkalimetal or their salts with weak acid; hydroxides of alkali earth metal ortheir salts with weak acid; and hydroxides of quaternary ammonium ortheir salts with weak acid. Specific examples thereof include sodiumhydroxide, potassium hydroxide, sodium carbonate, sodiumhydrogencarbonate, potassium carbonate, potassium hydrogencarbonate,cesium carbonate, tripotassium phosphate and tripotassium phosphatedihydrate. The amount of the base is preferably from 1 to 10 mols, andmore preferably from 2 to 6 mols, per mol of the N,O-diacyl compoundrepresented by the general formula (XVIII).

The solvent is not specifically limited as long as it does not exert anadverse influence on the reaction, and examples thereof include alcoholssuch as methanol, ethanol, propanol, isopropanol and butanol; amidessuch as dimethylformamide and dimethylacetamide; pyrrolidones such asN-methyl-2-pyrrolidone; ketone-sulfoxides such as acetone, ethyl methylketone and dimethyl sulfoxide; aromatic hydrocarbons such as benzene,toluene, xylene and mesitylene; ethers such as butyl methyl ether,diisopropyl ether, tetrahydrofuran, 1,4-dioxane, 1,2-dimethoxyethane andanisole; and water. These solvents can be used alone or in combination.The amount of the solvent is industrially preferably from about 50 to3000 parts by weight based on 100 parts by weight of the N,O-diacylcompound represented by the general formula (XVIII) in view ofoperability and economic efficiency. When using the solvent other thanwater, a suitable amount of water can also be added thereto. The amountof water is preferably from 0 to 10000 mols, and more preferably from 2to 6000 mols, per mol of the N,O-diacyl compound represented by thegeneral formula (XVIII).

The reaction temperature is preferably from 0 to 200° C., and morepreferably from 10 to 150° C.

(Step V)

The step V is the step of preparing3-N-methylamino-1-(2-thienyl)-1-propanol in the form of a racemate or anoptically active substance, which is represented by the general formula(IV), by hydrolyzing the propanolamine derivative represented by thegeneral formula (XVII) obtained in the step M or N in the presence of abase.

Examples of the base include hydroxides of alkali metal or their saltswith weak acid; hydroxides of alkali earth metal or their salts withweak acid; and hydroxides of quaternary ammonium or their salts withweak acid. Specific examples thereof include sodium hydroxide, potassiumhydroxide, sodium carbonate, sodium hydrogencarbonate, potassiumcarbonate, potassium hydrogencarbonate, cesium carbonate, tripotassiumphosphate and tripotassium phosphate dihydrate. The amount of the baseis preferably from 1 to 10 mols, and more preferably from 2 to 6 mols,per mol of the N-acyl compound represented by the general formula(XVII).

The solvent is not specifically limited as long as it does not exert anadverse influence on the reaction, and examples thereof include alcoholssuch as methanol, ethanol, propanol, isopropanol and butanol; amidessuch as dimethylformamide and dimethylacetamide; pyrrolidones such asN-methyl-2-pyrrolidone; ketone-sulfoxides such as acetone, ethyl methylketone and dimethyl sulfoxide; aromatic hydrocarbons such as benzene,toluene, xylene and mesitylene; ethers such as butyl methyl ether,diisopropyl ether, tetrahydrofuran, 1,4-dioxane, 1,2-dimethoxyethane andanisole; and water. These solvents can be used alone or in combination.The amount of the solvent is industrially preferably from about 50 to3000 parts by weight based on 100 parts by weight of the N-acyl compoundrepresented by the general formula (XVII) in view of operability andeconomic efficiency. When using the solvent other than water, a suitableamount of water can also be added thereto. The amount of water ispreferably from 0 to 10000 mols, and more preferably from 2 to 6000mols, per mol of the N-acyl compound represented by the general formula(XVII).

The reaction temperature is preferably from 0 to 200° C., and morepreferably from 10 to 150° C.

3-N-methylamino-1(thienyl)-1-propanol can be purified by vacuumdistillation. For example, the metal catalyst used in the asymmetricreduction cannot be easily removed by washing or recrystallization, butcan be easily removed by distillation. This is an effective meansbecause impurities such as coloranats can be easily removed.

The vacuum distillation can be conducted under reduced pressure within arange from 0.01 to 20 Torr, and preferably from 0.1 to 10 Torr in viewof operability. The temperature is from 50 to 200° C., and is preferablyfrom 70 to 180° C. in view of operability.

3-N-methylamino-1(thienyl)-1-propanol can be purified byrecrystallization. Impurities or colorants can be removed byrecrystallization, and thus a compound with high purity can be obtained.Since very slight coloration, which could not be removed bydistillation, can be completely removed, a compound with high purity canbe obtained when recrystallization is conducted after the distillationoperation.

The solvent, which can be used in the recrystallization, is notspecifically limited as long as it does not exert an adverse influenceon 3-N-methylamino-1(thienyl)-1-propanol, and examples thereof includemethanol, ethanol, propanol, isopropanol and butanol; amides such asdimethylformamide and dimethylacetamide; pyrrolidones such asN-methyl-2-pyrrolidone; ketone-sulfoxides such as acetone, ethyl methylketone and dimethyl sulfoxide; aromatic hydrocarbons such as benzene,toluene, xylene and mesitylene; ethers such as butyl methyl ether,diisopropyl ether, tetrahydrofuran, 1,4-dioxane, 1,2-dimethoxyethane andanisole; hydrocarbon solvents such as hexane and heptane; and water.These solvents can be used alone or in combination. The amount of thesolvent is industrially preferably from about 50 to 3000 parts by weightbased on 100 parts by weight of 3-N-methylamino-1(thienyl)-1-propanolrepresented by the general formula (IX) in view of operability andeconomic efficiency. Among these solvents, toluene is particularlypreferable in view of loss of the objective compound due to highdissolution and purification efficiency.

The recrystallization can be conducted at a dissolution temperaturewithin a range from 20° to 200° C., and preferably from 40 to 150° C.Under cooling, a crystal is deposited from the solution prepared bydissolving with heating, and the cooling temperature can be set within arange from −30 to 60° C. The cooling temperature is preferably set to30° C. or lower in view of yield and is preferably set to −15° C. orhigher in view of achievement of high purity. When the crystal is notformed, seed crystal can also be appropriately added.

EXAMPLES

Examples of the present invention will be described, but the presentinvention is not limited to the following Examples.

Example 1 Synthesis of(S)-N-[3-acetoxy-3-(2-thienyl)propyl]-N,N-dimethylamine

(S)-3-N,N-dimethylamino-1-(2-thienyl)-1-propanol (15 g, 81 mmol),triethylamine (9.0 g, 89 mmol) and chloroform (150 g) were charged in aflask and cooled to 5° C. To this was added dropwise acetyl chloride(10.8 g, 140 mmol) over 10 minutes. After reacting the mixture at 20° C.for 2 hours, the reaction solution was washed in turn with saturatedsodium bicarbonate water and saturated aqueous sodium chloride solution.The organic layer was concentrated under reduced pressure to obtain theobjective compound as a pale yellow oily product. The amount of theobjective compound was 16.9 g (yield: 92%).

The resulting compound was identified by the measurement by NMR. Theresults are shown below.

¹H NMR (270 MHz, DMSO-d6) 1.80-2.30 (m, 4H), 2.00 (s, 3H), 2.09 (s, 6H),6.02 (t, 1H), 7.0-7.5 (3H)

Example 2 Synthesis of2′,2′,2′-trichloroethyl(S)-N-[3-acetoxy-3-(2-thienyl)propyl]-N-methylcarbamate

(S)-N-[3-acetoxy-3-(2-thienyl)propyl]-N,N-dimethylamine (8.0 g, 35 mmol)obtained in Example 1, PROTON SPONGE (trade mark) (1.7 g, 8 mmol),trichloroethylchloroformate (22.2 g, 105 mmol) and toluene (80 g) werecharged in a flask and the mixture was stirred with heating at 70° C.for 2 hours. After cooling to room temperature, methanol (6.0 g) andtriethylamine (15.0 g, 150 mmol) were added, followed by stirring for 30minutes. The reaction solution was washed in turn with 2N-hydrochloricacid and saturated aqueous sodium chloride solution, and then theorganic layer was concentrated under reduced pressure and purified bycolumn chromatography to obtain the objective compound as a pale yellowoily product. The amount of the objective compound was 11.9 g (yield:87%).

The resulting compound was identified by the measurement by NMR. Theresults are shown below.

¹H NMR (270 MHz, DMSO-d6) 2.00 (s, 3H), 2.00-2.30 (m, 2H), 2.87-2.92 (d,3H), 3.29-3.40 (m, 2H), 4.81 (s, 2H), 5.92-5.96 (m, H), 7.0-7.5 (3H)

Example 3 Synthesis of(S)-N-[3-hydroxy-3-(2-thienyl)propyl]-N-methylacetamide

2′,2′,2′-trichloroethyl(S)-N-[3-acetoxy-3-(2-thienyl)propyl]-N-methylcarbamate(72 g, 0.18 mol) obtained in Example 2, Zn (120 g, 1.8 mol) and DMF (670g) were charged in a flask and formic acid (36 g, 0.78 mol) was addedunder cooling. After reacting the mixture at 20° C. for 2 hours, Zn wasremoved by filtration. The filtrate was concentrated and, afteradjusting the pH to 12 by adding 28 wt % ammonia water, the filtrate wasextracted with MTBE. The organic layer was concentrated under reducedpressure to obtain the objective compound as a pale yellow oily product.The amount of the objective compound was 35.5 g (yield: 90%).

The resulting compound was identified by the measurement by NMR. Theresults are shown below.

¹H NMR (270 MHz, CDCl₃) 1.84 (m, 1H), 1.97 (m, 1H), 2.01 (s, 3H), 2.95(s, 3H), 3.05 (m, 1H), 4.00 (m, 1H), 4.87 (dd 1H), 6.89-7.20 (3H)

Example 4 Synthesis of (S)-3-N-methylamino-1-(2-thienyl)-1-propanol

(S)-N-[3-hydroxy-3-(2-thienyl)propyl]-N-methylacetamide (21.3 g, 0.10mol) obtained in Example 3, KOH (112 g, 2.0 mol) and methanol (448 g)were charged in a flask and heated at 70° C. for 2 hours. The reactionsolution was concentrated under reduced pressure and, after adding water(70 g), the solution was extracted three times with MTBE (200 g). Theorganic layer was washed with 10 wt % aqueous sodium chloride solutionand then replaced with toluene and concentrated. After the depositedsolid was removed by filtration and the filtrate was concentrated,n-heptane was added and the deposited solid was filtered with suction.The resulting solid was washed with 30 ml of a solution mixture oftoluene/heptane (=5/95(v/v)) and then dried under reduced pressure toobtain the objective compound as a white solid. The amount of theobjective compound was 11.6 g (yield: 68%).

The resulting compound was identified by the measurement by NMR. Theresults are shown below.

¹H NMR (270 MHz, CDCl₃) 1.82-2.02 (m, 2H), 2.43 (s, 3H), 2.81-2.99 (m,2H), 5.20 (m, 1H), 6.89-7.20 (3H)

Example 5 Synthesis of 3-(N-benzylmethylamino)-1-(2-thienyl)-1-propanonehydrochloride

N-benzylmethylamine (36.9 g, 0.30 mmol) was dissolved in ethanol (40 ml)and a hydrochloride was formed by using 37% wt % hydrochloric acid (30.0g, 0.30 mmol). To the solution, acetylthiophene (30 g, 0.24 mmol),paraformaldehyde (10.8 g, 0.34 mmol), ethanol (20 ml) and 37 wt %hydrochloric acid (1.2 g, 0.01 mmol) were added and the mixture washeated under reflux at 80° C. for 4 hours. After the reaction solutionwas cooled to room temperature, the deposited crystal was filtered andwashed with ethanol. The crystal was dried at room temperature underreduced pressure to obtain the objective compound as a white crystal.The amount of the objective compound was 57.7 g (yield: 81.3%).

Example 6 (2) Synthesis of(RS)-3-N-methyl-N-benzylamino-1-(2-thienyl)-1-propanol

3-(N-benzylmethylamino)-1-(2-thienyl)-1-propanone hydrochloride (15.0 g,50.7 mmol) obtained in Example 5 was suspended in methanol (104 ml) andthe hydrochloride was neutralized by adding dropwise a solution preparedby dissolving sodium hydroxide (2.0 g, 50.7 mmol) in methanol (46 ml)was added dropwise under ice cooling. Then, sodium borohydride (3.8 g,101.4 mmol) was added and the mixture was stirred under ice cooling for2 hours. After the reaction solution was concentrated under reducedpressure, the residue was extracted with ethyl acetate and washed withsaturated aqueous sodium chloride solution (150 ml). The organic layerwas concentrated under reduced pressure to obtain the objective compoundas an oily product. The amount of the objective compound was 11.9 g(yield: 90.0%).

The resulting compound was identified by the measurement by NMR. Theresults are shown below.

¹HNMR (270 MHz, CDCl₃) 1.99 (dd, 2H), 2.24 (s, 3H), 2.73 (m, 2H), 3.54(dd, 2H), 5.15 (dd, 1H), 6.88-6.96 (m, 3H), 7.18-7.33 (m, 5H)

Example 7 (3) Synthesis of(RS)-N-[3-acetoxy-3-(2-thienyl)propyl]-N-methyl-N-benzylamine

(RS)-3-N-methyl-N-benzylamino-1-(2-thienyl)-1-propanol(6.6 g, 25.1 mmol)obtained in Example 6 was dissolved in THF (66 ml) and acetyl chloride(7.3 g, 101.3 mmol) was added dropwise under ice cooling, and then themixture was stirred under ice cooling for one hour. The reactionsolution was concentrated under reduced pressure, extracted with ethylacetate and then washed with 4 wt % sodium hydrogencarbonate water (180ml). The organic layer was concentrated under reduced pressure to obtainthe objective compound as an oily product. The amount of the objectivecompound was 7.16 g (yield: 94.0%).

The resulting compound was identified by the measurement by NMR. Theresults are shown below.

¹HNMR (270 MHz, CDCl₃) 1.93 (s, 3H), 2.09 (m, 2H), 2.15 (s, 3H), 2.37(m, 2H), 3.42 (t, 2H), 6.11 (dd, 1H), 6.87-6.98 (m, 3H), 7.18-7.26 (m,5H)

Example 8 (4) Synthesis of2′,2′,2′-trichloroethyl(RS)-N-[3-acetoxy-3-(2-thienyl)propyl]-N-methylcarbamate

(RS)-N-[3-acetoxy-3-(2-thienyl)propyl]-N-methyl-N-benzylamine (1.1 g,3.6 mmol) obtained in Example 7 was dissolved in acetonitrile (10 ml)and trichloroethyl chloroformate (0.5 ml, 3.6 mmol) was added dropwiseat 5° C. After stirring at room temperature for 2 hours, the reactionsolution was concentrated under reduced pressure to obtain the objectivecompound as an oily product. The amount of the objective compound was1.7 g.

The resulting compound was identified by the measurement by NMR. Theresults are shown below.

¹HNMR (270 MHz, CDCl₃) 2.14 (s, 3H), 2.22 (m, 2H), 2.96 (d, 3H), 3.37(m, 2H), 4.12 (s, 2H), 6.03 (dd, 1H), 6.92-7.06 (m, 3H), 7.13-7.30 (m,5H)

Example 9 (5) Synthesis of(RS)-N-[3-hydroxy-3-(2-thienyl)propyl]-N-methylacetamide

2′,2′,2′-trichloroethyl(RS)-N-[3-acetoxy-3-(2-thienyl)propyl]-N-methylcarbamate(0.5 g, 1.3 mmol) obtained in Example 8 was dissolved in acetic acid (5ml) and Zn (0.2 g) was suspended, and then, the mixture was stirred atroom temperature for 5 hours. The reaction solution was filtered and thefiltrate was concentrated under reduced pressure, and then the residuewas extracted with ethyl acetate. The extract was washed with 4 wt %sodium hydrogencarbonate water (30 ml) and concentrated under reducedpressure to obtain the objective compound as an oily product. The amountof the objective compound was 0.5 g.

The resulting compound was identified by the measurement by NMR. Theresults are shown below.

¹HNMR (270 MHz, CDCl₃) 2.10 (s, 3H), 2.03 (m, 2H), 2.95 (s, 3H), 3.04(dt, 2H), 3.64 (s, 1H), 4.73 (dd, 1H), 6.86-6.97 (m, 3H)

Example 10 Synthesis ofphenyl(RS)-N-[3-acetoxy-3-(2-thienyl)propyl]-N-methylcarbamate

(RS)-N-[3-acetoxy-3-(2-thienyl)propyl]-N-methyl-N-benzylamine (3.9 g,12.9 mmol) obtained in Example 7 was dissolved in acetonitrile (39 ml)and phenyl chloroformate (2.0 g, 12.9 mmol) was added dropwise at 5° C.After stirring the mixture at room temperature for one hour, thereaction solution was concentrated under reduced pressure to obtain theobjective compound as an oily product. The amount of the objectivecompound was 5.2 g.

The resulting compound was identified by the measurement by NMR. Theresults are shown below.

¹HNMR (500 MHz, CDCl₃) 1.98 (s, 3H), 2.23 (m, 2H), 3.03 (s, 3H), 3.44(m, 2H), 6.10 (m, 1H), 6.91-7.10 (m, 3H), 7.17-7.38 (m, 5H)

Example 11 Synthesis ofethyl(RS)-N-[3-acetoxy-3-(2-thienyl)propyl]-N-methylcarbamate

(RS)-N-[3-acetoxy-3-(2-thienyl)propyl]-N-methyl-N-benzylamine (1.0 g,3.3 mmol) obained in Example 7 was dissolved in acetonitrile (10 ml) andethyl chloroformate (0.4 g, 3.3 mmol) was added dropwise at 5° C. Afterstirring the mixture at room temperature for 2 hours, the reactionsolution was concentrated under reduced pressure to obtain the objectivecompound as an oily product. The amount of the objective compound was1.1 g.

The resulting compound was identified by the measurement by NMR. Theresults are shown below.

¹HNMR (270 MHz, CDCl₃) 1.13 (t, 3H), 1.94 (s, 3H), 2.08 (m, 2H), 2.77(s, 3H), 3.22 (m, 2H), 4.00 (dd, 2H), 5.92 (dd, 1H), 6.85 (dd, 2H), 6.97(m, 1H)

Example 12 (8) Synthesis ofphenyl(RS)-N-[3-phenyloxycarbonyloxy-3-(2-thienyl)propyl]-N-methylcarbamate

(RS)-3-N,N-dimethylamino-1(2-thienyl)-1-propanol (10 g, 54.0 mmol) wasdissolved in acetonitrile (100 ml) and triethylamine (5.5 g, 54.0 mmol)was added under ice cooling. Furthermore, phenyl chloroformate (21.1 g,134.9 mmol) was added dropwise at 5° C. and the mixture was stirred atroom temperature for 2 hours. After the completion of the reaction, anaqueous 2 wt % sodium hydroxide solution (356 g) was added, followed bystirring under ice cooling for 0.5 hours. The reaction solution wasseparated between layers and the organic layer was concentrated underreduced pressure to obtain the objective compound as an oily product.The amount of the objective compound was 25.5 g.

The resulting compound was identified by the measurement by NMR. Theresults are shown below.

¹HNMR (270 MHz, CDCl₃) 2.31 (m, 2H), 3.06 (s, 3H), 3.60 (m, 2H), 6.02(m, 1H), 6.74-7.00 (m, 3H), 7.09-7.44 (m, 10H)

Example 13 (9) (RS)-3-N-methylamino-1-(2-thienyl)-1-propanol

phenyl(RS)-N-[3-phenyloxycarbonyloxy-3-(2-thienyl)propyl]-N-methylcarbamate(50.2 mmol) obtained in Example 12 was dissolved in a 24 wt % potassiumhydroxide-methanol solution (231.7 g) and the solution was heated underreflux at 80° C. for 2 hours. The reaction solution was concentratedunder reduced pressure and, after removing a salt with toluene,n-heptane was added to obtain the objective compound as a white solid.The amount of the objective compound was 0.9 g (yield: 44.4%).

The resulting compound was identified by the measurement by NMR. Theresults are shown below.

¹HNMR (270 MHz, CDCl₃) 1.92 (m, 2H), 2.43 (s, 3H), 2.90 (m, 2H), 3.20(s, 2H), 5.18 (m, 1H), 6.90 (m, 2H), 7.20 (m, 1H)

Example 14 Synthesis of(S)-3-N-methyl-N-benzylamino-1-(2-thienyl)-1-propanol

A 0.5M 2-propanol solution (40 μL) containing potassium hydroxidedissolved therein, (R,R)-diphenylethylenediamine (2.1 mg, 0.01 mmol),3-(N-benzylmethylamino)-1-(2-thienyl)-1-propanone (873 mg, 5.0 mmol)obtained in Example 5 and 2-propanol (3 ml) were charged in a Schlenkreaction tube under an argon gas flow and, after deaeration andreplacement by argon, RuCl₂ ((R)-BINAP)(dmf)n (9.6 mg, 0.01 mmol) wasadded to prepare a reaction solution. The solution was completelydissolved by repeatedly conducting the deaeration and replacement byargon. The solution was transferred to a 100 ml glass autoclave andhydrogen was introduced to a predetermined pressure, thereby initiatingthe reaction. After stirring at 28° C. for 6 hours and returning tonormal temperature, the objective compound was obtained.

Optical purity of the resulting compound was determined by the HPLCprocess using an optically active column. As a result, optical puritywas high such as 96% ee.

Example 15 Synthesis of(S)-N-[3-acetoxy-3-(2-thienyl)propyl]-N-methyl-N-benzylamine

In the same manner as in Example 7, except that(S)-3-N-methyl-N-benzylamino-1-(2-thienyl)-1-propanol obtained inExample 14 was used in place of(RS)-3-N-methyl-N-benzylamino-1-(2-thienyl)-1-propanol, the titledcompound was obtained. The yield was 96%.

Example 16 Synthesis ofphenyl(S)-N-[3-acetoxy-3-(2-thienyl)propyl]-N-methylcarbamate

In the same manner as in Example 10, except that(S)-N-[3-acetoxy-3-(2-thienyl)propyl]-N-methyl-N-benzylamine obtained inExample 15 was used in place of(RS)-N-[3-acetoxy-3-(2-thienyl)propyl]-N-methyl-N-benzylamine, thetitled compound was obtained. The yield was 92%.

Example 17 Synthesis ofphenyl(S)-N-[3-phenyloxycarbonyloxy-3-(2-thienyl)propyl]-N-methylcarbamate

In the same manner as in Example 12, except that(S)-3-N,N-dimethylamino-1(2-thienyl)-1-propanol was used in place of(RS)-3-N,N-dimethylamino-1(2-thienyl)-1-propanol, the titled compoundwas obtained. The yield was 58%.

Example 18 Synthesis of (S)-3-N-methylamino-1-(2-thienyl)-1-propanol

(S)-3-N,N-dimethylamino-1(2-thienyl)-1-propanol (55 g) and triethylamine(30 g) were added to MTBE (618 g) and phenyl chloroformate (116 g) wasadded dropwise while stirring at −5° C. The reaction solution wasstirred at room temperature for 4 hours and 2 wt % sodium hydroxide(1955 g) was added dropwise while maintaining at 5° C. or lower,followed by stirring for 30 minutes. The aqueous layer was removed and asolution mixture of potassium hydroxide (333 g)/methanol (1000 g) wasadded to the organic layer, followed by refluxing under stirring for 2hours. The reaction solution was concentrated under reduced pressureand, after adding water (381 g) to the residue, the solution wasextracted three times with MTBE (762 g). The organic layers werecombined, washed with water (190 g) and then mixed with toluene (1434g). The solvent was distilled off under reduced pressure until theamount of the residue reached 568 g, and then insolubles were removed byfiltration. The filtrate was concentrated under reduced pressure andheptane (1007 g) was added, followed by stirring at −15° C. to obtainthe objective compound as a pale yellow solid. The amount of theobjective compound was 28 g.

Example 19 Synthesis ofisopropyl(RS)-N-[3-isopropyloxycarbonyloxy-3-(2-thienyl)propyl]-N-methylcarbamate

(R,S)-3-N,N-dimethylamino-1-(2-thienyl)-1-propanol (0.93 g, 5 mmol),triethylamine (0.66 g, 6.5 mmol) and THF (9.3 g) were charged in a flaskand then cooled to 5° C. Then, isopropyl chloroformate (2.14 g, 17.5mmol) was added dropwise over 10 minutes. After the mixture was reactedat 20° C. for 2 hours, the reaction solution was added dropwise in a 5wt % sodium hydroxide solution containing MTBE dissolved therein and theorganic layer was extracted. The organic layer was washed with saturatedaqueous sodium chloride solution and then concentrated under reducedpressure to obtain the objective compound as a pale yellow oily product.The amount of the objective compound was 1.80 g.

The resulting compound was identified by the measurement by NMR. Theresults are shown below.

¹H NMR (270 MHz, CDCl₃) 1.07-1.34 (m, 12H), 2.15-2.30 (m, 2H), 2.85(s,3H), 3.18-3.30 (m, 2H), 4.79-4.90 (2H), 5.79-5.84 (m, 1H), 6.9-7.3 (3H)

Example 20 Synthesis ofisobutyl(RS)-N-[3-isobutyloxycarbonyloxy-3-(2-thienyl)propyl]-N-methylcarbamate

(R,S)-3-N,N-dimethylamino-1-(2-thienyl)-1-propanol (0.93 g, 5 mmol),triethylamine (0.66 g, 6.5 mmol) and THF (9.3 g) were charged in a flaskand then cooled to 5° C. Then, isobutyl chloroformate (2.39 g, 17.5mmol) was added dropwise over 10 minutes. After the mixture was reactedat 20° C. for 2 hours, the reaction solution was added dropwise in a 5wt % by sodium hydroxide solution containing MTBE dissolved therein andthe organic layer was extracted. The organic layer was washed withsaturated aqueous sodium chloride solution and then concentrated underreduced pressure to obtain the objective compound as a pale yellow oilyproduct. The amount of the objective compound was 1.92 g.

The resulting compound was identified by the measurement by NMR. Theresults are shown below.

¹H NMR (270 MHz, CDCl₃) 0.88-0.96 (m, 12H), 1.82-1.95 (m, 2H), 2.10-2.30(m, 2H), 2.87 (s, 3H), 3.18-3.40 (m, 2H), 3.80-3.88 (4H), 5.80-5.85 (m,1H), 6.9-7.3 (3H)

Example 21 Synthesis ofisobutyl(RS)-N-[3-isobutyloxycarbonyloxy-3-(2-thienyl)propyl]-N-methylcarbamate

(R,S)-3-N,N-dimethylamino-1-(2-thienyl)-1-propanol (55.6 g, 0.30 mol),triethylamine (39.5 g, 0.39 mol) and toluene (278 g) were charged in aflask and then cooled to 5° C. Then, isobutyl chloroformate (123 g, 0.90mol) was added dropwise so that the inner temperature did not exceed 15°C. After the mixture was reacted at 25° C. for 6 hours, an aqueous 10 wt% sodium hydroxide solution (360 g, 0.90 mmol) was added to the reactionsolution and the organic layer was extracted. The organic layer wasconcentrated under reduced pressure to obtain the objective compound asa pale yellow oily product. The amount of the objective compound was 142g and the yield of the objective compound was 96.0%. The yield of theobjective compound was determined by high-performance liquidchromatography.

Example 22 Synthesis of (S)-3-N-methylamino-1(thienyl)-1-propanol

(S)-3-N,N-dimethylamino-1-(2-thienyl)-1-propanol (50.0 g, 0.27 mol),triethylamine (35.5 g, 0.35 mmol) and toluene (249 g) were charged in aflask, and then isobutyl chloroformate (110.5 g, 0.81 mmol) was addeddropwise so that the inner temperature became 20 to 30° C. After themixture was reacted at 25° C. for 6 hours, an aqueous 10 wt % NaOHsolution (324 g, 0.81 mmol) was added dropwise to the reaction solutionand the organic layer was extracted. The organic layer was concentratedunder reduced pressure to obtain 125.6 g of a pale yellow oily product.To this was added a 25 wt % potassium hydroxide-methanol solution (603g, 2.67 mol), followed by heating under reflux at the inner temperatureof 75° C. for 3.5 hours. After the reaction solution was concentratedunder reduced pressure until the amount reached 447 g, water (303 g) wasadded and the solution was replaced and concentrated until the inneramount reached 394 g. To the solution was added toluene (202 g), andthen the organic layer was extracted. The organic layer was concentratedunder reduced pressure to obtain 54.7 g of(S)-3-N-methylamino-1(thienyl)-1-propanol as a pale yellow solid. Thepale yellow solid was subjected to vacuum distillation to obtain 41.5 gof a fraction at a vapor phase temperature within a range from 100 to130° C. under reduced pressure of 2 to 4 Torr. The fraction was mixedwith toluene (103 g), dissolved with heating at 60° C. and then cooledto 30° C. Then, a seed crystal of(S)-3-N-methylamino-1(thienyl)-1-propanol was added to deposit acrystal. After cooling to 5° C., the crystal was filtered with suctionand washed with toluene (20.8 g) cooled to 5° C. The crystal was driedunder reduced pressure to obtain 36.8 g of(S)-3-N-methylamino-1(thienyl)-1-propanol as a colorless crystal (yield:79.6%).

Example 23 Synthesis of (S)-3-N,N-dimethylamino-1-(2-thienyl)-1-propanol

trans-RuCl₂((R)-xylBINAP) ((R)-DAIPEN) (30.5 mg, 0.025 mmol), a2-propanol solution (100 ml), a t-butanol solution (7.5 ml, 7.5 mmol) of1.0M t-butoxy potassium and3-(N-dimethylamino)-1-(2-thienyl)-1-propanone (22.9 g, 0.125 mol) werecharged in a glass autoclave and, after repeatedly conducting deaerationand replacement by argon, hydrogen was introduced to a predeterminedpressure, thereby to initiate the reaction. After stirring at 28° C. for6 hours, the reaction solution was returned to normal temperature andnormal pressure. After the reaction solution was concentrated, heptanewas added and the deposited solid was filtered with suction. Theresulting solid was dried under reduced pressure to obtain the objectivecompound. The amount of the objective compound was 18.5 g (yield:80.0%). Optical purity of the resulting compound was determined by theHPLC process using an optically active column. As a result, opticalpurity was high such as 99% ee.

(R)-DAIPEN denotes(R)-1-isopropyl-2,2-di(p-methoxyphenyl)ethylenediamine, and xylBINAPdenotes 2,2′-bis(di-3,5-xylylphosphino)-1,1′-binaphthyl.

INDUSTRIAL APPLICABILITY

As described in detail above, according to the present invention, it ismade possible to provide means for preparing a racemate or an opticallyactive substance (S- or R-isomer) of3-N-methylamino-1-(2-thienyl)-1-propanol in a simple manner at low costand in high yield.

1. A propanolamine derivative represented by the following generalformula (I):

wherein R¹ represents any of a hydrogen atom, an acyl group having 1 to8 carbon atoms, an alkyloxycarbonyl group having 1 to 8 carbon atomswhich may have a substituent and a phenyloxycarbonyl group which mayhave a substituent, and R² represents any of a hydrogen atom, an alkylgroup having 1 to 8 carbon atoms, a benzyl group which may have asubstituent, an acyl group having 1 to 8 carbon atoms, analkyloxycarbonyl group having 1 to 8 carbon atoms which may have asubstituent and a phenyloxycarbonyl group which may have a substituent,with the exception that R¹ is a hydrogen atom and R² is a methyl groupor a hydrogen atom.
 2. The propanolamine derivative according to claim1, which is the S-isomer.
 3. The propanolamine derivative according toclaim 1, wherein R¹ and R² each independently represents analkyloxycarbonyl group having 1 to 8 carbon atoms which may have asubstituent, or a phenyloxycarbonyl group which may have a substituent.4. The propanolamine derivative according to claim 3, wherein R¹ and R²each independently represents a functional group represented by thefollowing general formula (II):—COOCH₂CH_(m)X_(n)  (II) wherein X represents a halogen atom, m and neach independently represents an integer of 0 to 3 and the sum of themis
 3. 5. The propanolamine derivative according to claim 4, wherein R¹and R² represent a 2,2,2-trichloroethyloxycarbonyl group.
 6. Thepropanolamine derivative according to claim 3, wherein R¹ and R²represent a phenyloxycarbonyl group.
 7. The propanolamine derivativeaccording to claim 3, wherein R¹ and R² represent anisopropyloxycarbonyl group.
 8. The propanolamine derivative according toclaim 3, wherein R¹ and R² represent an isobutyloxycarbonyl group. 9.The propanolamine derivative according to claim 3, wherein R¹ and R²represent an ethyloxycarbonyl group.
 10. The propanolamine derivativeaccording to claim 1, wherein R¹ is a hydrogen atom and R² is an acylgroup having 1 to 8 carbon atoms.
 11. The propanolamine derivativeaccording to claim 10, wherein R² is an acetyl group.
 12. Thepropanolamine derivative according to claim 1, wherein R¹ is a hydrogenatom and R² is an alkyloxycarbonyl group having 1 to 8 carbon atomswhich may have a substituent, or a phenyloxycarbonyl group which mayhave a substituent.
 13. The propanolamine derivative according to claim12, wherein R² is a phenyloxycarbonyl group.
 14. The propanolaminederivative according to claim 12, wherein R² is a2,2,2-trichloroethyloxycarbonyl group.
 15. The propanolamine derivativeaccording to claim 12, wherein R² is an isopropyloxycarbonyl group. 16.The propanolamine derivative according to claim 12, wherein R² is anisobutyloxycarbonyl group.
 17. The propanolamine derivative according toclaim 1, wherein R¹ is an acyl group having 1 to 8 carbon atoms and R²is any of a hydrogen atom, an alkyl group having 1 to 8 carbon atoms, abenzyl group which may have a substituent, an alkyloxycarbonyl grouphaving 1 to 8 carbon atoms which may have a substituent, aphenyloxycarbonyl group which may have a substituent and an acyl grouphaving 1 to 8 carbon atoms.
 18. The propanolamine derivative accordingto claim 17, wherein R is an alkyl group having 1 to 8 carbon atoms or abenzyl group which may have a substituent.
 19. The propanolaminederivative according to claim 18, wherein R² is a benzyl group which mayhave a substituent.
 20. The propanolamine derivative according to claim17, wherein R² is an alkyloxycarbonyl group having 1 to 8 carbon atomswhich may have a substituent or a phenyloxycarbonyl group which may havea substituent.
 21. The propanolamine derivative according to claim 20,wherein R² is a functional group represented by the following generalformula (II):—COOCH₂CH_(m)X_(n)  (II) wherein X represents a halogen atom, m and neach independently represents an integer of 0 to 3 and the sum of themis
 3. 22. The propanolamine derivative according to claim 21, wherein R²is a 2,2,2-trichloroethyloxycarbonyl group.
 23. The propanolaminederivative according to claim 20, wherein R² is a phenyloxycarbonylgroup.
 24. The propanolamine derivative according to claim 20, whereinR² is an isopropyloxycarbonyl group.
 25. The propanolamine derivativeaccording to claim 20, wherein R² is an isobutyloxycarbonyl group. 26.The propanolamine derivative according to claim 17, wherein R¹ and R²each independently represents an acyl group having 1 to 8 carbon atoms.27. The propanolamine derivative according to claim 1, wherein R¹ is ahydrogen atom and R² is a benzyl group which may have a substituent. 28.A process for preparing 3-N-methylamino-1-(2-thienyl)-1-propanol, whichcomprises preparing 3-N-methylamino-1-(2-thienyl)-1-propanol representedby the following general formula (IV):

using or via the propanolamine derivative of claim
 1. 29. A process forpreparing 3-N-methylamino-1-(2-thienyl)-1-propanol represented by thefollowing general formula (IV):

which comprises the step of eliminating the substituent R³ of apropanolamine derivative represented by the following general formula(III):

wherein R³ represents an alkyl group having 1 to 8 carbon atoms whichmay have a substituent or a benzyl group which may have a substituent.30. The process for preparing 3-N-methylamino-1-(2-thienyl)-1-propanolaccording to claim 29, wherein both of the propanolamine derivativesrepresented by the general formulas (III) and (IV) are the S-isomer. 31.A process for preparing 3-N-methylamino-1-(2-thienyl)-1-propanol, whichcomprises the steps (E) of reacting acetylthiophene, a dialkylaminerepresented by the following general formula (V):HNCH₃R³  (V) wherein R³ represents an alkyl group having 1 to 8 carbonatoms which may have a substituent or a benzyl group which may have asubstituent, and formalin under acidic conditions to obtain a ketonecompound represented by the following general formula (VI):

wherein R³ is as defined above; the step (F) of reducing the ketonecompound to obtain a propanolamine derivative represented by thefollowing general formula (III):

wherein R³ is as defined above; and the step (S) of eliminating thesubstituent R³ of the propanolamine derivative represented by thegeneral formula (III) to obtain 3-N-methylamino-1-(2-thienyl)-1-propanolrepresented by the following general formula (IV).


32. A process for preparing(S)-3-N-methylamino-1-(2-thienyl)-1-propanol, which comprises the step(E) of reacting acetylthiophene, a dialkylamine represented by thefollowing general formula (V):HNCH₃R³  (V) wherein R³ represents an alkyl group having 1 to 8 carbonatoms which may have a substituent or a benzyl group which may have asubstituent, and formalin under acidic conditions, to obtain a ketonecompound represented by the following general formula (VI):

wherein R³ is as defined above; the step (F) of reducing the ketonecompound to obtain a propanolamine derivative represented by thefollowing general formula (III):

wherein R³ is as defined above; the step (G) of optically resolving thepropanolamine derivative represented by the general formula (III) usingan optically active organic acid to obtain a propanolamine derivative inthe form of the S-isomer represented by the following general formula(VII):

wherein R³ is as defined above; and the step (I) of eliminating thesubstituent R³ of the propanolamine derivative in the form of theS-isomer to obtain (S)-3-N-methylamino-1-(2-thienyl)-1-propanolrepresented by the following general formula (VIII).


33. A process for preparing(S)-3-N-methylamino-1-(2-thienyl)-1-propanol, which comprises the step(E) of reacting acetylthiophene with a dialkylamine represented by thefollowing general formula (V):HNCH₃R³  (V) wherein R³ represents an alkyl group having 1 to 8 carbonatoms which may have a substituent or a benzyl group which may have asubstituent under acidic conditions to obtain a ketone compoundrepresented by the following general formula (VI):

wherein R³ is as defined above; the step (H) of reacting the ketonecompound with hydrogen in the presence of an asymmetrical hydrogenationcatalyst containing a transition metal, thereby conducting asymmetricalhydrogenation of the ketone compound to obtain a propanolaminederivative in the form of the S-isomer represented by the followinggeneral formula (VII):

wherein R³ is as defined above; and the step (I) of eliminating thesubstituent R³ of the propanolamine derivative in the form of theS-isomer to obtain (S)-3-N-methylamino-1-(2-thienyl)-1-propanolrepresented by the following general formula (VIII).


34. The process for preparing(S)-3-N-methylamino-1-(2-thienyl)-1-propanol according to claim 33,wherein, in the step (H), the asymmetrical hydrogenation of the ketonecompound is conducted in the presence of a base and an optically activenitrogen-containing compound, in addition to the asymmetricalhydrogenation catalyst.
 35. The process for preparing3-N-methylamino-1-(2-thienyl)-1-propanol according to any one of claims29 and 31 to 33, which comprises the step of reductively eliminating thesubstituent R³ of the propanolamine derivative represented by thegeneral formula (III) or (VII).
 36. The process for preparing3-N-methylamino-1-(2-thienyl)-1-propanol according to any one of claims29 and 31 to 33, which comprises the step of reacting the propanolaminederivative represented by the general formula (III) or (VII) with achloroformic acid derivative represented by the following generalformula (IX):ClCOOR⁴  (IX) wherein R⁴ represents an alkyl group having 1 to 8 carbonatoms which may have a substituent or a phenyl group which may have asubstituent, and hydrolyzing the intermediate without isolation toobtain 3-N-methylamino-1-(2-thienyl)-1-propanol.
 37. The process forpreparing 3-N-methylamino-1-(2-thienyl)-1-propanol according to any oneof claims 29 and 31 to 33, which further comprises the step of reactingthe propanolamine derivative represented by the general formula (III) or(VII) with a chloroformic acid derivative represented by the followinggeneral formula (X):ClCOOCH₂CH_(m)X_(n)  (X) wherein X represents a halogen atom, m and neach independently represents an integer of 0 to 3 and the sum of themis 3, and subjecting the intermediate todehalogenation/alkyloxycarbonylation and hydrolysis without isolation toobtain 3-N-methylamino-1-(2-thienyl)-1-propanol.
 38. The process forpreparing 3-N-methylamino-1-(2-thienyl)-1-propanol according to any oneof claims 29 and 31 to 33, which comprises the step (J) of reacting thepropanolamine derivative represented by the general formula (III) or(VII) with a chloroformic acid derivative represented by the followinggeneral formula (IX):ClCOOR⁴  (IX) wherein R⁴ represents an alkyl group having 1 to 8 carbonatoms which may have a substituent or a phenyl group which may have asubstituent, to obtain a propanolamine derivative represented by thefollowing general formula (XI):

wherein R⁴ is as defined above; and the step (R) of hydrolyzing thepropanolamine derivative represented by the general formula (XI) toobtain 3-N-methylamino-1-(2-thienyl)-1-propanol.
 39. The process forpreparing 3-N-methylamino-1-(2-thienyl)-1-propanol according to any oneof claims 29 and 31 to 33, which comprises the step (J) of reacting thepropanolamine derivative represented by he general formula (III) or(VII) with a chloroformic acid derivative represented by the followinggeneral formula (IX):ClCOOR⁴  (IX) wherein R⁴ represents an alkyl group having 1 to 8 carbonatoms which may have a substituent or a phenyl group which may have asubstituent to obtain a propanolamine derivative represented by thefollowing general formula (XI):

wherein R⁴ is as defined above; the step (O) of treating thepropanolamine derivative represented by the general formula (XI) with abase in the amount of 0.1 to 1.9 equivalents based on the compound, toobtain a propanolamine derivative represented by the following generalformula (XII):

wherein R⁴ is as defined above; and the step (Q) of hydrolyzing thepropanolamine derivative represented by the general formula (XII) toobtain 3-N-methylamino-1-(2-thienyl)-1-propanol.
 40. The process forpreparing 3-N-methylamino-1-(2-thienyl)-1-propanol according to any oneof claims 29 and 31 to 33, which comprises the step (K) of reacting thepropanolamine derivative represented by the general formula (III) or(VII) with an alkylcarboxylic acid chloride or alkylcarboxylic anhydriderepresented by the following general formula (XIII):ClCOR⁶  (XIII) wherein R⁶ represents an alkyl group having 1 to 8 carbonatoms or a phenyl group, or the general formula (XIV):(R⁶CO)₂O  (XIV) wherein R⁶ is as defined above, to obtain apropanolamine derivative represented by the following general formula(XV):

wherein R³ and R⁶ are as defined above; the step (L) of reacting thepropanolamine derivative represented by the general formula (XV) with achloroformic acid derivative represented by the following generalformula (IX):ClCOR⁴  (IX) wherein R⁴ represents an alkyl group having 1 to 8 carbonatoms which may have a substituent or a phenyl group which may have asubstituent, to obtain a propanolamine derivative represented by thefollowing general formula (XVI):

wherein R⁴ and R⁶ are as defined above); and the step (T) of hydrolyzingthe propanolamine derivative represented by the general formula (XVI) toobtain 3-N-methylamino-1-(2-thienyl)-1-propanol.
 41. The process forpreparing 3-N-methylamino-1-(2-thienyl)-1-propanol according to any oneof claims 29 and 31 to 33, which comprises the step (K) of reacting thepropanolamine derivative represented by the general formula (III) or(VII) with an alkylcarboxylic acid chloride or alkylcarboxylic anhydriderepresented by the following general formula (XIII):ClCOR⁶  (XIII) wherein R⁶ represents an alkyl group having 1 to 8 carbonatoms or a phenyl group, or the general formula (XIV):(R⁶CO)₂O  (XIV) wherein R⁶ is as defined above, to obtain apropanolamine derivative represented by the following general formula(XV):

wherein R³ and R⁶ are as defined above; the step (M) of reducing thepropanolamine derivative represented by the general formula (XV) toobtain a propanolamine derivative represented by the following generalformula (XVII):

wherein R⁶ is as defined above; and the step (V) of hydrolyzing thepropanolamine derivative represented by the general formula (XVII) toobtain 3-N-methylamino-1-(2-thienyl)-1-propanol.
 42. The process forpreparing 3-N-methylamino-1-(2-thienyl)-1-propanol according to any oneof claims 29 and 31 to 33, which comprises the step (K) of reacting apropanolamine derivative represented by the general formula (III) or(VII) with an alkylcarboxylic acid chloride or alkylcarboxylic anhydriderepresented by the following general formula (XIII):ClCOR⁶  (XIII) wherein R⁶ represents an alkyl group having 1 to 8 carbonatoms or a phenyl group, or the general formula (XIV):(R⁶CO)₂O  (XIV) wherein R⁶ is as defined above, to obtain apropanolamine derivative represented by the following general formula(XV):

wherein R³ and R⁶ are as defined above; the step (M) of reducing thepropanolamine derivative represented by the general formula (XV) toobtain a propanolamine derivative represented by the following generalformula (XVII):

wherein R⁶ is as defined above; the step (P) of reacting thepropanolamine derivative represented by the general formula (XVII) withan alkylcarboxylic acid chloride or alkylcarboxylic anhydriderepresented by the general formula (XIII) or (XIV) to obtain apropanolamine derivative represented by the following general formula(XVIII):

wherein R⁶ is as defined above; and the step (U) of hydrolyzing thepropanolamine derivative represented by the general formula (XVIII) toobtain 3-N-methylamino-1-(2-thienyl)-1-propanol.
 43. The process forpreparing 3-N-methylamino-1-(2-thienyl)-1-propanol according to any oneof claims 29 and 31 to 33, which comprises the step (K) of reacting thepropanolamine derivative represented by the general formula (III) or(VII) with an alkylcarboxylic acid chloride or alkylcarboxylic anhydriderepresented by the following general formula (XIII):ClCOR⁶  (XIII) wherein R⁶ represents an alkyl group having 1 to 8 carbonatoms or a phenyl group, or the general formula (XIV):(R⁶CO)₂O  (XIV) wherein R⁶ is as defined above, to obtain apropanolamine derivative represented by the following general formula(XV):

wherein R³ and R⁶ are as defined above; the step (N) of reacting thepropanolamine derivative represented by the general formula (XV) with achloroformic acid derivative represented by the following generalformula (X):ClCOOCH₂CH_(m)X_(n)  (X) wherein X represents a halogen atom, m and neach independently represents an integer of 0 to 3 and the sum of themis 3, to obtain a propanolamine derivative represented by the followinggeneral formula (XIX):

wherein R⁶, X, m and n are as defined above, and conducting the cleavagereaction of the urethane moiety and the transfer reaction of the acylgroup of the propanolamine derivative represented by the general formula(XIX) to obtain a propanolamine derivative represented by the followinggeneral formula (XVII):

wherein R⁶ is as defined above; and the step (V) of hydrolyzing thepropanolamine derivative represented by the general formula (XVII) toobtain 3-N-methylamino-1-(2-thienyl)-1-propanol.
 44. The process forpreparing 3-N-methylamino-1-(2-thienyl)-1-propanol according to any oneof claims 29 and 31 to 33, which comprises the step (K) of reacting thepropanolamine derivative represented by the general formula (III) or(VII) with an alkylcarboxylic acid chloride or alkylcarboxylic anhydriderepresented by the following general formula (XIII):ClCOR⁶  (XIII) wherein R⁶ represents an alkyl group having 1 to 8 carbonatoms or a phenyl group, or the general formula (XIV):(R⁶CO)₂O  (XIV) wherein R⁶ is as defined above, to obtain apropanolamine derivative represented by the following general formula(XV):

wherein R³ and R⁶ are as defined above; the step (N) of reacting thepropanolamine derivative represented by the general formula (XV) with achloroformic acid derivative represented by the following generalformula (X):ClCOOCH₂CH_(m)X_(n)  (X) wherein X represents a halogen atom, m and neach independently represents an integer of 0 to 3 and the sum of themis 3, to obtain a propanolamine derivative represented by the followinggeneral formula (XIX):

wherein R⁶, X, m and n are as defined above, and conducting the cleavagereaction of the urethane moiety and the transfer reaction of the acylgroup of the propanolamine derivative represented by the general formula(XIX) to obtain a propanolamine derivative represented by the followinggeneral formula (XVII):

wherein R⁶ is as defined above; the step (P) of reacting thepropanolamine derivative with the general formula (XVII) with analkylcarboxylic acid chloride or alkylcarboxylic anhydride representedby the general formula (XIII) or (XIV) to obtain a propanolaminederivative represented by the following general formula (XVIII):

wherein R⁶ is as defined above; and the step (U) of hydrolyzing thepropanolamine derivative represented by the general formula (XVIII) toobtain 3-N-methylamino-1-(2-thienyl)-1-propanol.
 45. A process forpreparing a propanolamine derivative represented by the followinggeneral formula (XI):

wherein R⁴ is as defined below, which comprises the step of reacting apropanolamine derivative represented by the following general formula(III):

wherein R³ represents an alkyl group having 1 to 8 carbon atoms whichmay have a substituent or a benzyl group which may have a substituent,with a chloroformic acid derivative represented by the following generalformula (IX):ClCOOR⁴  (IX) wherein R⁴ represents an alkyl group having 1 to 8 carbonatoms which may have a substituent or a phenyl group which may have asubstituent.
 46. The process for preparing a propanolamine derivativeaccording to claim 45, wherein R⁴ of the chloroformic acid derivativerepresented by the general formula (IX) is a phenyl group, an isopropylgroup or an isobutyl group.
 47. The process for preparing apropanolamine derivative according to claim 45, wherein both of thepropanolamine derivatives represented by the general formulas (III) and(XI) are the S-isomer.
 48. A process for preparing a propanolaminederivative represented by the following general formula (XII):

wherein R⁴ is as defined below, which comprises the step of reacting apropanolamine derivative represented by the following general formula(XI):

wherein R⁴ represents an alkyl group having 1 to 8 carbon atoms whichmay have a substituent or a phenyl group which may have a substituent,with a base.
 49. The process for preparing a propanolamine derivativeaccording to claim 48, wherein both of the propanolamine derivativesrepresented by the general formulas (XI) and (XII) are the S-isomer. 50.A process for preparing 3-N-methylamino-1-(2-thienyl)-1-propanolrepresented by the following general formula (IV):

which comprises the step of hydrolyzing a propanolamine derivativerepresented by the following general formula (XII):

wherein R⁴ represents an alkyl group having 1 to 8 carbon atoms whichmay have a substituent or a phenyl group which may have a substituent.51. The process for preparing 3-N-methylamino-1-(2-thienyl)-1-propanolaccording to claim 50, wherein both of the propanolamine derivativesrepresented by the general formulas (XII) and (IV) are the S-isomer. 52.A process for preparing 3-N-methylamino-1-(2-thienyl)-1-propanolrepresented by the following general formula (IV)

which comprises hydrolyzing a propanolamine derivative represented bythe following general formula (XI):

wherein R⁴ represents an alkyl group having 1 to 8 carbon atoms whichmay have a substituent or a phenyl group which may have a substituent.53. The process for preparing 3-N-methylamino-1-(2-thienyl)-1-propanolaccording to claim 52, wherein both of the propanolamine derivativesrepresented by the general formulas (XI) and (IV) are the S-isomer. 54.A process for preparing a propanolamine derivative represented by thefollowing general formula (XV):

wherein R³ and R⁶ are as defined below, which comprises the step ofreacting a propanolamine derivative represented by the following generalformula (III):

wherein R³ represents an alkyl group having 1 to 8 carbon atoms whichmay have a substituent or a benzyl group which may have a substituent,with an alkylcarboxylic acid chloride or alkylcarboxylic anhydriderepresented by the following general formula (XIII):ClCOR⁶  (XIII) wherein R⁶ represents an alkyl group having 1 to 8 carbonatoms or phenyl group, or the general formula (XIV):(R⁶CO)₂O  (XIV) wherein R⁶ is as defined above.
 55. The process forpreparing a propanolamine derivative according to claim 54, wherein bothof the propanolamine derivatives represented by the general formulas(III) and (XV) are the S-isomer.
 56. A process for preparing apropanolamine derivative represented by the following general formula(XVI):

wherein R⁴ and R⁶ are as defined below, which comprises the step ofreacting a propanolamine derivative represented by the following generalformula (XV):

wherein R³ represents an alkyl group having 1 to 8 carbon atoms whichmay have a substituent or a benzyl group which may have a substituent,and R⁶ represents an alkyl group having 1 to 8 carbon atoms or phenylgroup, with a chloroformic acid derivative represented by the followinggeneral formula (IX):ClCOOR⁴  (IX) wherein R⁴ represents an alkyl group having 1 to 8 carbonatoms which may have a substituent or a phenyl group which may have asubstituent.
 57. The process for preparing a propanolamine derivativeaccording to claim 56, wherein both of the propanolamine derivativesrepresented by the general formulas (XV) and (XVI) are the S-isomer. 58.A process for preparing a propanolamine derivative represented by thefollowing general formula (XVII):

wherein R⁶ is as defined below, which comprises the step of reducing apropanolamine derivative represented by the following general formula(XV):

wherein R³ represents an alkyl group having 1 to 8 carbon atoms whichmay have a substituent or a benzyl group which may have a substituent,and R⁶ represents an alkyl group having 1 to 8 carbon atoms or a phenylgroup.
 59. The process for preparing a propanolamine derivativeaccording to claim 58, wherein both of the propanolamine derivativesrepresented by the general formulas (XV) and (XVII) are the S-isomer.60. A process for preparing 3-N-methylamino-1-(2-thienyl)-1-propanolrepresented by the following general formula (IV):

which comprises the step of hydrolyzing a propanolamine derivativerepresented by the following general formula (XVII):

wherein R⁶ represents an alkyl group having 1 to 8 carbon atoms or aphenyl group.
 61. The process for preparing3-N-methylamino-1-(2-thienyl)-1-propanol according to claim 60, whereinboth of the propanolamine derivatives represented by the generalformulas (XVII) and (IV) are the S-isomer.
 62. A process for preparing apropanolamine derivative represented by the following general formula(XVIII):

wherein R⁶ is as defined below, which comprises the step of reacting apropanolamine derivative represented by the following general formula(XVII):

wherein R⁶ represents an alkyl group having 1 to 8 carbon atoms orphenyl group, with an alkylcarboxylic acid chloride or alkylcarboxylicanhydride represented by the following general formula (XIII):ClCOR⁶  (XIII) wherein R⁶ is as defined above, or the general formula(XIV):(R⁶CO)₂O  (XIV) wherein R⁶ is as defined above.
 63. The process forpreparing a propanolamine derivative according to claim 62, wherein bothof the propanolamine derivatives represented by the general formulas(XVII) and (XVIII) are the S-isomer.
 64. A process for preparing3-N-methylamino-1-(2-thienyl)-1-propanol represented by the followinggeneral formula (IV):

which comprises the step of hydrolyzing a propanolamine derivativerepresented by the following general formula (XVIII):

wherein R⁶ represents an alkyl group having 1 to 8 carbon atoms or aphenyl group.
 65. The process for preparing3-N-methylamino-1-(2-thienyl)-1-propanol according to claim 64, whereinboth of the propanolamine derivatives represented by the generalformulas (XVIII) and (IV) are the S-isomer.
 66. A process for preparinga propanolamine derivative represented by the following general formula(XVII):

wherein R⁶ is as defined below, which comprises the step of conductingthe cleavage reaction of the urethane moiety and the transfer reactionof the acyl group of the propanolamine derivative represented by thegeneral formula (XIX):

wherein R⁶ represents an alkyl group having 1 to 8 carbon atoms orphenyl group, X represents a halogen atom, m and n each independentlyrepresents an integer of 0 to 3 and the sum of them is
 3. 67. Theprocess for preparing a propanolamine derivative according to claim 66,wherein both of the propanolamine derivatives represented by the generalformulas (XIX) and (XVII) are the S-isomer.
 68. A process for preparing3-N-methylamino-1-(2-thienyl)-1-propanol represented by the followinggeneral formula (IV):

which comprises the step of hydrolyzing a propanolamine derivativerepresented by the following general formula (XVI):

wherein R⁴ represents an alkyl group having 1 to 8 carbon atoms whichmay have a substituent or a phenyl group which may have a substituent,and R⁶ represents an alkyl group having 1 to 8 carbon atoms or a phenylgroup.
 69. The process for preparing3-N-methylamino-1-(2-thienyl)-1-propanol according to claim 68, whereinboth of the propanolamine derivatives represented by the generalformulas (XVI) and (IV) are the S-isomer.
 70. A process for preparing apropanolamine derivative in the form of the S-isomer represented by thefollowing general formula (VII):

wherein R³ is as defined above, which comprises the step of reacting aketone compound represented by the following general formula (VI):

wherein R³ represents an alkyl group having 1 to B carbon atoms whichmay have a substituent or a benzyl group which may have a substituent,with the exception that R³ is a methyl group, with hydrogen in thepresence of an asymmetrical hydrogenation catalyst containing atransition metal, thereby conducting asymmetrical hydrogenation of theketone compound.
 71. The process for preparing a propanolaminederivative in the form of the S-isomer according to claim 70, whereinthe asymmetrical hydrogenation of the ketone compound is conducted inthe presence of a base and an optically active nitrogen-containingcompound, in addition to the asymmetrical hydrogenation catalyst. 72.The process for preparing a propanolamine derivative in the form of theS-isomer according to claim 71, wherein the base is any of a hydroxide,an alkoxylated compound, a mercaptized compound, a naphthylated compoundand a quaternary ammonium salt of alkali metal or alkali earth metal.73. The process for preparing a propanolamine derivative in the form ofthe S-isomer according to claim 71, wherein the optically activenitrogen-containing compound is an optically active amine compound. 74.The process for preparing a propanolamine derivative in the form of theS-isomer according to claim 71, wherein the optically active aminecompound is (R)-1-isopropyl-2,2-di(p-methoxyphenyl)ethylenediamine. 75.The process for preparing a propanolamine derivative in the form of theS-isomer according to claim 70, wherein R³ is a benzyl group in thepropanolamine derivatives represented by the general formulas (VI) and(VII).
 76. The process for preparing a propanolamine derivative in theform of the S-isomer according to claim 70, wherein the asymmetricalhydrogenation catalyst is a complex of the group VIII transition metal.77. The process for preparing a propanolamine derivative in the form ofthe S-isomer according to claim 76, wherein the group VIII transitionmetal is ruthenium.
 78. The process for preparing a propanolaminederivative in the form of the S-isomer according to claim 76, whereinthe asymmetrical hydrogenation catalyst has an optically active ligand.79. The process for preparing a propanolamine derivative in the form ofthe S-isomer according to claim 78, wherein the optically active ligandis a phosphine ligand.
 80. The process for preparing a propanolaminederivative in the form of the S-isomer according to claim 79, whereinthe optically active phosphine ligand is2,2′-bis(di-3,5-xylylphosphino)-1,1′-binaphthyl(xylBINAP).
 81. A processfor preparing a propanolamine derivative in the form of the S-isomerrepresented by the following general formula (VII):

wherein R³ is as defined below, which comprises the step of obtaining adiastereomer salt of a propanolamine derivative represented by thefollowing general formula (III):

wherein R³ represents an alkyl group having 1 to 8 carbon atoms whichmay have a substituent or a benzyl group which may have a substituent,with the exception that R³ is a methyl group, with an optically activeorganic acid, and optically resolving the diastereomer salt.
 82. Theprocess for preparing a propanolamine derivative in the form of theS-isomer according to claim 81, wherein R³ is a benzyl group in thepropanolamine derivatives represented by the general formulas (III) and(VII).
 83. The process for preparing a propanolamine derivative in theform of the S-isomer according to claim 81, wherein the optically activeorganic acid is any of an optically active carboxylic acid, an opticallyactive sulfonic acid and an optically active phosphonic acid, which isrepresented by the following general formula (XXI):

wherein D represents any of COO⁻, SO₃ ⁻ and PO₃H⁻, A, B, C eachindependently represents any of a hydrogen atom, a substituted orunsubstituted linear or branched alkyl group having 1 to 10 carbonatoms, a halogen atom, an alkoxy group, a hydroxyl group, a nitro group,a carboxyl group and a substituted or unsubstituted phenyl or naphthylgroup, a substituent of the alkyl group, the phenyl group and thenaphthyl group represents any of a linear or branched alkyl group having1 to 10 carbon atoms, a halogen atom, an alkoxy group, a hydroxyl group,a nitro group, a carboxyl group and a sulfonate group, A, B, C and(CH₂)_(n)-DH each represent a different substituent, n represents 1 or0, and the symbol * represents an asymmetric carbon.
 84. The process forpreparing a propanolamine derivative in the form of the S-isomeraccording to claim 83, wherein the optically active organic acid is anoptically active mandelic acid derivative represented by the followinggeneral formula (XXII):

wherein Z represents any of a hydrogen atom, a linear or branched alkylgroup having 1 to 10 carbon atoms, a halogen atom, an alkoxy group, ahydroxyl group, a nitro group and a benzoyl group, and the symbol *represents an asymmetric carbon.